1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
CARDIOVASCULAR AND RENAL DRUGS
ADVISORY COMMITTEE
Holiday Inn
2
P A R T I C I P A N T S
Dornette Spell-LeSane, M.H.A., NP-C,
Executive
Secretary
Jeffrey S. Borer, M.D., Acting Chairman
Steve Nissen, M.D.
Alan T. Hirsch, M.D.
Thomas Fleming, Ph.D.
Maria H. Sjogren, M.D.
Jonathan
Sackner-Bernstein, M.D.
John R. Teerlink M.D.
Susanna L. Cunningham, Ph.D.
William R. Hiatt, M.D.
Beverly H. Lorell, M.D.
Thomas Pickering, M.D.
Ronald Portman, M.D.
Paul Watkins, M.D., Ph.D.
Jose Vega, M.D.
FDA
Participants
Dr.
Mark Avigan
Dr.
Florence Houn
Dr.
Joyce Korvick
Dr.
Kathy Robie-Suh
3
C O N T E N T S
AGENDA ITEM
PAGE
Call to Order and Introductions - Jeffrey
S. Borer,
M.D., Acting Chair 5
Conflict of Interest Statement - Dornette
Spell-LeSane, NP-C, Executive
Secretary 8
Welcome and Comments - Norman Stockbridge,
M.D.,
Acting Director, Division of
Cardiovascular and
Renal Drug Products, FDA 13
Sponsor Presentation
Introduction - Hamish Cameron, M.D., Vice
President, Exanta 15
Clinical Pharmacology - Troy Sarich,
Ph.D.,
Director, Clinical Pharmacology 24
Efficacy - Jay Horrow, M.D., Senior
Director,
Clinical Development 43
Safety - Sunita Sheth, M.D., Senior
Director,
Clinical Development 97
Benefit and Risk Anticoagulation -
Jonathan L.
Halperin, M.D.,
FDA Presentation
Risk/Benefit Assessment - Ruyi He, M.D.,
Medical
Officer, Division of Gastrointestinal and
Coagulation Drug Products 172
Risk Management of Hepatotoxic Drugs -
Kate
Gelperin, M.D., M.P.H., Medical
Epidemiologist,
Division of Drug Risk Evaluation 282
Drug-Induced Liver Toxicity - Paul
Watkins, M.D.,
Verne S. Caviness Distinguished Professor
of
Medicine, Director, General Clinical
Research
Center,
Medical Center 301
4
C O N T E N T S
(Continued)
AGENDA ITEM
PAGE
Questions from the Committee --
Open Public Hearing 184
Charge to the Committee - Joyce Korvick,
M.D.,
M.P.H., Acting Division Director,
Division of
Gastrointestinal and Coagulation Drug
Products, FDA 318
Committee Discussion 319
Break --
Committee Questions/Summary 320
Adjournment
414
5
P R O C E E D I N G
S
DR.
BORER: It's
call the meeting to order. This is the Cardiovascular and
Renal Drugs Advisory Committee
meeting, and we will discuss New Drug
Application
(NDA) 21-686, proposed trade name Exanta
(ximelagatran) by AstraZeneca, for the
proposed
indication of the prevention of venous
thromboembolism in
patients undergoing knee replacement
surgery, the prevention of stroke and other
thromboembolic complications associated
with atrial
fibrillation, and the long-term secondary
prevention of venous thromboembolic
events after
standard treatment following an episode
of acute
venous thromboembolic event.
We'll begin by introducing
everybody at
the table. In this meeting, the Cardio/Renal
Committee actually is advising the GI
Division as
well as Cardio/Renal, in fact, primarily
the GI
Division, so we have more people at the
table than
we sometimes do. Maybe we can each say our name
and what we're doing here, and we'll
start with Dr.
6
Vega on the far side.
DR. VEGA:
I'm Jose Vega. I'm the
industry representative on the committee,
and I'm
from Amgen.
DR. PICKERING: Tom Pickering from
DR. PORTMAN: Ron Portman from the
DR. HIATT: Bill Hiatt, University of
DR. LORELL: Bev Lorell, Harvard Medical
School, and also Guidant Corporation.
DR. SACKNER-BERNSTEIN: Jonathan
Sackner-Bernstein,
in
DR.
CUNNINGHAM: Susanna Cunningham. I am
the consumer representative
on the committee, and
I'm from the
DR. NISSEN: I'm Steve Nissen. I'm a
cardiologist at the Cleveland Clinic.
DR. WATKINS: Paul Watkins.
I'm a
hepatology consultant from
7
Carolina-Chapel Hill.
DR. BORER: Jeff Borer, cardiologist,
MS.
SPELL-LeSANE: Dornette Spell-LeSane,
Executive Secretary for the
committee.
DR. TEERLINK: John Teerlink, University
of California-San Francisco, and
DR. FLEMING: Tom Fleming, University of
DR. HIRSCH: Alan Hirsch, cardiologist and
vascular medicine specialist at the
University of
DR. AVIGAN: Mark Avigan, Office of Drug
Safety at the FDA.
DR. STOCKBRIDGE: I'm Norman
Stockbridge,
the Acting Director of the Division of
Cardio/Renal
Drug Products at FDA.
DR. HOUN: I'm Florence Houn. I'm the
Office Director for Drug Evaluation III.
DR. KORVICK: Joyce Korvick, Acting
Director, Division of Gastrointestinal
Coagulation
8
Drug Products.
DR. ROBIE-SUH: Kathy Robie-Suh, Acting
Deputy Director, Division of Gastrointestinal
and
Coagulation Drug Products.
DR. BORER: Thank you very much.
We have many people at the
table. I'm
going to remind everyone that when you
speak, you
should press the button on your microphone,
and
when you're done, turn it off, please,
unless you
want to say something because that's the
only way
I'm going to know that you want to if you
press the
button and I see the light.
We'll go on to the conflict of
interest
statement. Dornette Spell-LeSane, the Executive
Secretary of the Cardio/Renal Drug
Advisory
Committee, will present the conflict of
interest.
MS. SPELL-LeSANE: Good morning.
The
following announcement addresses the
issue of
conflict of interest and is made part of
the record
to preclude even the appearance of such
at this
meeting.
Based on the submitted agenda and all
financial interests reported by the committee
9
participants, it has been determined that
all
interests in firms regulated by the
Center for Drug
Evaluation and Research present no
potential for an
appearance of a conflict of interest at
this
meeting, with the following exceptions:
In accordance with 18 U.S.C.
Section
208(b)(3), full waivers have been granted
to the
following participants. Please note that all of
the consulting and speaking activities
waived are
unrelated to Exanta and its competing
products:
Dr. William Hiatt for
consulting for two
competitors for which he receives less
than $10,001
per year per firm;
Dr. Thomas Pickering for
serving on a
competitor's advisory board for which he
receives
less than $10,001 per year;
Dr. Ronald Portman for
consulting for a
competitor for which he receives less
than $10,001
per year;
Dr. Thomas Fleming for
consulting for four
competitors, he receives less than
$10,001 per year
per firm;
10
Dr. Sackner-Bernstein for
consulting for
the sponsor and a competing firm, he
receives less
than $10,001 per year per firm. Also, for his
Speaker Bureau activities for a
competitor, he
receives less than $10,001 to $50,000 per
year;
Dr. Jeffrey Borer for serving on a
steering committee for a competitor, he
receives
less than $10,001 per year;
Dr. Alan Hirsch for lecturing
for the
sponsor, for which he receives less than
$5,001 per
year.
For lecturing for three competing firms, he
receives less than $5,001 per year for
serving on
two Speaker Bureaus, and from $5,001 to
$10,001 for
one Speakers Bureau. Two consulting agreements for
two competing firms, he receives less
than $10,001
per year for one consulting, and from
$10,001 to
$50,000 per year for the other.
In accordance with 18 U.S.C.
208(b)(3), a
limited waiver has been granted to Dr.
Paul Watkins
for serving on two advisory boards for a
competing
firm.
He receives less than $10,001 per year for
one and greater than $50,000 per year for
the
11
other.
Under the terms of this limited waiver, Dr.
Watkins will be permitted to participate
in the
committee's discussion of Exanta. He is, however,
excluded from voting.
Lastly, in accordance with 18
U.S.C.
Section 208(b)(1), full waivers have been
granted
to the following participants for
interests
unrelated to Exanta and its competing
products:
Dr. John Teerlink for speaking
for two
competitors, he receives less than
$10,001 per year
from one, and from $10,001 to $50,000 per
year from
the other. Also, for his consulting for a
competitor for which he receives between
$10,000 to
$50,000 per year;
Dr. Maria Sjogren for
consulting for a
competitor for which she receives less
than $10,001
per year.
A copy of the waiver statement
may be
obtained by submitting a written request
to the
agency's Freedom of Information Office,
Room 12A-30
of the
discussions involve any other products or
firms not
12
already on the agenda for which FDA
participants
have a financial interest, the participants
are
aware of the need to exclude themselves
from such
involvement, and their exclusion will be
noted for
the record.
We would also like to note that
Dr. Jose
Vega has been invited to participate as
an industry
representative acting on behalf of
regulated
industry.
Dr. Vega is employed by Amgen.
With respect to all other
participants, we
ask in the interest of fairness that they
address
any current or previous financial
involvement with
any firm whose products they may wish to
comment
upon.
Thank you.
DR. BORER: Thank you very much, Dornette.
That was about the longest conflict of
interest
statement that I can remember.
But we still are five minutes
ahead,
Norman Stockbridge, the Acting Director
of the
Division of Cardiovascular and Renal Drug
Products.
13
DR. STOCKBRIDGE: I'll see if I can keep
us on schedule. Good morning and welcome to what
promises to be an interesting meeting on
behalf of
the Divisions of Cardio/Renal Drug
Products and GI
and Coagulation Drug Products. I want to thank
members of the Cardio/Renal Advisory
Committee,
consultants, and the sponsor for their
participation.
I do need to acknowledge retirement
of
four members from the Advisory
Committee: Alan
Hirsch is here today, a couple of chairs
down to my
left; Steve Nissen is over at the middle
of the
table there; Paul Armstrong would be here
today
except that Homeland Security discovered
that he's
a Canadian.
[Laughter.]
DR. STOCKBRIDGE: And, finally, there is
our Chairman, Dr. Jeff Borer. Dr. Borer's service
to the committee began in 1977, an era in
which
members still sported powdered wigs.
[Laughter.]
DR. STOCKBRIDGE: I can't quite tell from
14
the records where he cast his first vote,
but in
that year, the committee heard arguments
on
potassium and atropine.
As tokens of our appreciation,
Ms.
Spell-LeSane has for each of you some
actual
certificates signed by our Acting
Commissioner and
some virtual plaques that look just like
this one.
So on behalf of Cardio/Renal, the Food
and Drug
Administration, and a grateful nation,
thanks to
you all.
[Applause.]
DR. NISSEN: Norman, I'm not from Canada,
but I'm from Cleveland, and it's really
close to
Canada.
Will you please not tell Homeland Security
about me?
DR. BORER: Thank you very much, Norman,
and thank you for staying way on time
because we
are now 17 minutes ahead of schedule,
which is
good.
The sponsor has a 90-minute presentation.
We'll try to allow you to move along as
well as we
can, but undoubtedly there will be some
clarification
questions. We ought to try to hold the
15
questions that we ask to clarification
issues
during the presentation, if we can, and
we can get
into the meat of the substantive
discussion
afterwards.
The presentation will be
introduced by Dr.
Cameron, the Vice President of Exanta.
DR. CAMERON: Thank you, Mr. Chairman,
members of the committee, ladies and
gentlemen,
good morning. I'm Dr. Hamish Cameron, the Vice
President of Exanta at AstraZeneca, and
with my
colleagues we're pleased to present
ximelagatran, a
new oral anticoagulant.
After a 20-year journey to
discover and
develop this new medicine and half a
century
without significant innovation in this
area of
therapeutics, we believe ximelagatran,
the first
oral treatment in the new drug class
direct
thrombin inhibitors is a real advance in
oral
anticoagulation.
Ximelagatran has a mechanism of
action
that's quite different from the vitamin K
antagonists like warfarin and can provide
the first
16
oral alternative to warfarin, today's
only option
for long-term anticoagulation.
Anticoagulation is the major
approach to
both the prevention and treatment of
thromboembolic
disease, a disease that's the final
common pathway
for many life-threatening conditions,
like stroke,
myocardial infarction, and pulmonary
embolism. And
it's the commonest cause of death and
disability in
America today.
At the outset we must ask: Given the
widespread availability of the vitamin K
antagonists like warfarin, why is there a
need for
a new oral anticoagulant? Warfarin is a highly
efficacious anticoagulant and one of the
top ten
most prescribed drugs, used in nearly
every medical
specialty by 3 million patients in the
U.S.
involving 32 million prescriptions every
year. But
it's been in the top five, sometimes
number one, in
the lists of drugs associated with
significant
interactions, medication errors, serious
bleeding,
and hospital admissions.
Warfarin's profile of
unpredictable
17
kinetics and dynamics; food, alcohol, and
multiple
drug interactions; together with its
acknowledged
narrow therapeutic index--too little
warfarin, and
there's the risk of residual clotting;
too much,
and the risk of bleeding--all these drive
the need
for a lifetime of INR coagulation
monitoring and
never-ending individual dose titration.
To put it simply, you don't get
the
benefit of warfarin from just taking the
tablet.
Its overall effectiveness is highly
dependent on
how it's managed. And it's this fact that frames
the innovation of ximelagatran.
Many patients and doctors fear
the risk of
bleeding that comes with unpredictable
anticoagulation.
This fear tends to result in
under-treatment, quite paradoxical in
high-risk
elderly patients, or in about half the
overall
patients eligible for warfarin, little or
no
treatment at all.
We started a discovery program
targeting
thrombin in 1985. We sought to develop a new oral
anticoagulant, an alternative to
warfarin, with a
18
profile that would allow fixed dosing
without
coagulation monitoring, further supported
by a low
potential for food and drug interactions.
We looked for a rapid onset and
offset of
action to simplify turning
anticoagulation on and
off, which is one of the challenging
aspects of
warfarin treatment. And all this had to be
achieved with an acceptable bleeding
profile.
Today, we believe these
objectives have
been met by the Ximelagatran Development
Program,
involving 82 clinical studies and
enrolling over
30,000 subjects. More than 17,000 people received
ximelagatran with 3,500 patients dosed
for over a
year.
And our longest patient exposure has now
reached five years.
Here are the three proposed
indications in
the
current NDA, spanning exposures from days to
several years. The first is the long-term
secondary prevention of venous
thromboembolism,
VTE, after standard treatment for an
acute episode.
Treatment of acute VTE involved six
months of
anticoagulation with warfarin, but at the
start of
19
this development in 1999, it was unknown
whether
longer treatment would be
beneficial. And so a
placebo-controlled study, THRIVE III, was
conducted. As you'll see, this study demonstrated
a highly significant reduction of VTE
during
longer-term prophylactic treatment. And as a
placebo-controlled study, it provides the
strongest
evidence of ximelagatran's antithrombotic
efficacy.
The second indication is the
prevention of
VTE after knee replacement surgery. Patients
without anticoagulant prophylaxis run a
high risk
of DVT and pulmonary embolism, and in the
U.S.,
warfarin is the most widely used drug,
started late
on the day of surgery to reduce this
risk. In two
warfarin controlled studies, EXULT A and
EXULT B,
we've shown a significant reduction of
VTE risk for
ximelagatran compared with warfarin.
The third indication is the
prevention of
stroke and other thromboembolic
complications
associated with atrial fibrillation. Here with the
large SPORTIF III and V trials, we've
shown the
efficacy of ximelagatran to be comparable
to
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well-controlled warfarin.
Across these pivotal, mainly
outcomes-based studies involving
independent
endpoint adjudication, we've demonstrated
ximelagatran's antithrombotic efficacy
and recorded
a favorable leading profile, equivalent
to and in
some cases better than the
comparator. We detected
a
signal of raised hepatic enzymes with chronic
treatment, and so we've conducted a very
detailed
analysis, consulted with experts, and
believe the
risk can be adequately managed.
I should highlight that in your
briefing
packs and our safety presentation, we've
included
data from two other large studies in
other
indications, not for consideration today,
but which
contribute nearly 4,000 patients. The THRIVE
treatment study is the first pivotal
study looking
at initial VTE treatment, and the second
study is
soon to start, while the ESTEEM trial is
a Phase II
dose guiding study in the post-acute
coronary
syndrome setting.
These data enrich the overall
safety
21
assessment, including patients from very
different
clinical settings and a wide range of
characteristics, and
we're going to review all the key
data in the presentations that follow.
We believe ximelagatran with
its
predictable anticoagulant effects and
favorable
bleeding profile has a positive
benefit/risk in the
proposed indications, provided it's used properly.
And part of that proper use is the
introduction of
an appropriate risk management program
directed
towards the hepatic risk.
We made an initial proposal
with our
submission which had been developed with
extensive
external consultation and field testing,
but we
fully recognize, following the
deliberations of
this committee and further discussions
with FDA,
the program will need to be developed and
strengthened further before an approach
can be
finalized in the best interests of
patients. We
are committed to working with FDA to
achieve the
most appropriate risk management program
to ensure
the safe use of ximelagatran because
patient safety
22
is, has been, and always will be
AstraZeneca's top
priority when we introduce new medicines
into
clinical practice.
Since 1998, we've met
repeatedly with FDA
throughout ximelagatran's development--in
end of
Phase II meetings, a pre-NDA interaction,
and
there's a meeting coming up to discuss
the nature
and extent of the risk management
program. The NDA
was submitted in December 2003.
I should add that all the same
data are
now being reviewed in Europe by the
French agency
before a mutual recognition
procedure. But there's
one difference worth noting. Given the quite
different clinical practice regarding
anticoagulant
prophylaxis in orthopedic surgery,
separate
developments were conducted in the U.S.
and Europe.
The European program, reflecting local
practice and
starting treatment much closer to the
time of
operation, was the subject of a separate
earlier
regulatory submission and completed the
mutual
recognition procedure in May this
year. And the
first orthopedic launch was in Germany in
June.
23
Now, you have the data on this
program in
your briefing packs, but with the
significant
timing, comparator, and formulation
differences,
our presentations today will largely
focus on the
data directly relevant to the NDA
orthopedic
surgery application.
Here's the agenda for our
session. Dr.
Troy Sarich will review clinical
pharmacology; Dr.
Jay Horrow, efficacy; and Dr. Sunita Sheth,
safety;
allowing an overall evaluation of
ximelagatran in
the three requested indications. Dr. Jonathan
Halperin from Mount Sinai Medical Center
will then
give his views on the benefit/risk of
ximelagatran
in clinical practice. And throughout our
presentations, we hope to cover for you
all the
specific comments raised by the agency in
their
briefing document.
In addition to Dr. Halperin,
we're also
joined by other consultants: Dr. Gerald Faich, Dr.
Lloyd Fisher, Dr. Peter Kowey, and Dr.
James Lewis.
In summary, then, ximelagatran
is a new
oral anticoagulant that provides the
first
24
alternative to warfarin after 50
years. We believe
a total review of the available clinical
data
supports a positive benefit/risk in each
of the
proposed indications. Ximelagatran can enhance
health care delivery in America and
throughout the
world to help prevent a range of
debilitating and
life-threatening thromboembolic diseases.
Thank you. Now I'd like to introduce Dr.
Troy Sarich for clinical pharmacology.
DR. SARICH: Good morning.
I'm Dr. Troy
Sarich, Director of Clinical Pharmacology
at
AstraZeneca. I'll now present an overview of the
clinical pharmacology of ximelagatran in
which we
have performed both the traditional clinical
pharmacology studies and population
pharmacokinetic
analyses.
Ximelagatran is an oral direct
thrombin
inhibitor. It's rapidly bioconverted to the active
form, melagatran. The bioconversion, which is
Cytochrome P-450 independent, involves both
de-esterification and a reduction that
occurs
throughout the body.
25
The exposure to melagatran is
linear
across a dose range from 5 to 98 milligrams
ximelagatran. The pharmacokinetics are predictable
over time with repeated dosing, and the
elimination
half-life of melagatran is approximately
4 to 5
hours in patients. Once formed, melagatran is
primarily eliminated from plasma by a
glomerular
filtration.
Thrombin is a key enzyme in the
coagulation cascade. It converts fibrinogen to
fibrin, activates platelets, and induces
its own
generation. Melagatran directly inhibits thrombin
as a classic competitive and
reversible-binding
enzyme inhibitor. There's a direct relationship
between the pharmacokinetics and
pharmacodynamics
of ximelagatran. Its active when present in
plasma, and once eliminated from plasma,
its effect
is gone.
Preclinical investigations
indicated an
antithrombotic effect of melagatran at
approximately 0.05
micromolar, with increasing effect up
to approximately 0.5 micromolar.
26
In humans, ximelagatran
prolongs clotting
time assays. The thrombin time assay shown here
was prolonged in a linear manner at
concentrations
as low as 0.05 micromolar. In addition, melagatran
prolongs in a concentration-dependent
manner the
activated partial thromboplastin time,
although it
is less sensitive.
Additional investigations using
pharmacodynamic models in humans
demonstrated
evidence for inhibition of thrombin
generation
indicated by concentration-dependent
reduction and
thrombin-antithrombin complex levels and
platelet
activation indicated by
concentration-dependent
reduction in beta thromboglobulin levels
at
melagatran concentrations at or near 0.05
micromolar. All together, it was clear from these
data that direct inhibition of thrombin
by
melagatran resulted in the intended
anticoagulant
activity in humans.
After oral administration, the
inactive
pro drug ximelagatran is rapidly
eliminated from
plasma as it is biotransformed to
melagatran, shown
27
in blue, with peak melagatran
concentrations
occurring approximately 2 to 3 hours
post-dosing.
Melagatran plasma concentrations greater
than 0.05
micromolar are achieved early after oral
ximelagatran,
indicating a rapid onset of action which
simplifies the initiation of oral
anticoagulation.
Concentrations remain above 0.05
micromolar
throughout the dosing interval,
supporting a
twice-daily dosing regimen.
And as shown here, the rapid
onset of
action of oral ximelagatran is not
altered when
co-administered with food. Although there's an
approximately one-hour delay in the time
to C-max,
there is no effect on the AUC or Cmax of
melagatran.
Warfarin's well-recognized drug
interaction profile is largely related to
its
metabolism by the Cytochrome P-450 system
and its
high plasma protein binding. Ximelagatran is not
metabolized by and does not inhibit the
major
Cytochrome P-450 enzymes listed
here. It also has
low plasma protein binding, and along
with the
28
majority of melagatran eliminated from
plasma by
glomerular filtration, this leads to an
inherently
low potential for drug interactions.
Our investigations have
identified
pharmacokinetic interactions with erythromycin
and
azithromycin. Erythromycin results in an
80-percent or less than twofold increase
in
melagatran plasma levels, with a smaller,
40- to
60-percent increase with azithromycin.
These changes are within the
overall range
of melagatran exposures in patients, and
as
outlined in detail in your briefing
document,
investigation into the potential impact
of this
pharmacokinetic interaction found no
signal for
increases bleeding events or increased
ALT
elevations in the approximately 230
patients
receiving ximelagatran and macrolide
antibiotics in
the long-term studies. These data do not suggest
an important clinical impact of these
pharmacokinetic interactions.
We have conducted many other
interaction
studies where we've found no significant
29
pharmacokinetic interactions. As shown by the mean
melagatran AUC ration and the 90-percent
confidence
interval within or slightly outside the
0.8 to 1.25
no interaction interval. The drugs investigated
include alcohol, common cardiovascular
medications,
an NSAID, a sedative, and several
antibiotics.
These results are consistent with
population
pharmacokinetic analyses indicating a
lack of
interaction with commonly used
comedications in the
patient studies. Taken together, these data
suggest that ximelagatran has a low
potential for
drug interactions.
Melagatran is primarily renally
eliminated
from plasma, and so we've carefully
investigated
the impact of renal function on the
pharmacokinetics of
ximelagatran. In the three patient
populations under consideration today,
melagatran
exposure increases as calculated
creatinine
clearance decreases. For this reason, severe renal
impairment, a calculated creatinine clearance
less
than 30 mLs per minute, was an exclusion
criteria
for our clinical studies, and we're
currently
30
investigating an alternative dosing
strategy in
that population.
It's notable that we've
gathered
considerable experience with ximelagatran
in
patients with mild to moderate renal
impairment as
approximately 45 percent of the Phase III
patient
population had a calculated creatinine
clearance
between 30 and 80 mLs per minute. The median
exposures in these patients are about 1.5
to 2.5
times higher, respectively, than patients
with
normal renal function, but there's
considerable
overlap in melagatran exposure between
groups,
suggesting dose adjustment was not
necessary.
We've also studied the
potential effects
on the pharmacokinetics of ximelagatran
within
other special populations, and other than
differences in renal function between
groups, we
have not identified other important
effects of age,
gender, race, obesity--as measured using
body mass
index--or body weight on the
pharmacokinetics of
ximelagatran.
The agency has suggested there
should be a
31
dose adjustment for ximelagatran in
patients with
renal impairment given the higher levels
of
melagatran in these patients. But I'd like to show
you why a fixed dose, as used in our
clinical
studies, is appropriate across the
patient
populations studied.
We do agree with the agency's
assessment
that there's no need for dose adjustment
in
orthopedic surgery patients and that
there was no
increased bleeding related to melagatran
exposure
in VTE secondary prevention
patients. We do
acknowledge an association between
increasing
melagatran exposure and increasing
incidence of
major bleeding in atrial fibrillation
patients.
But this relationship appears confounded
by the
correlation between melagatran exposure
and the
age-related decrease in calculated
creatinine
clearance.
Shown here from the SPORTIF
trials is the
relationship between calculated
creatinine
clearance and major bleeding. As you can see,
major bleeding increased with declining
renal
32
function whether patients received
ximelagatran or
INR-controlled warfarin. This suggests the
increase in melagatran concentrations in
patients
with renal impairment is not associated
with
increased bleeding versus INR-controlled
warfarin.
It's also important to note
that stroke
risk increased with decreasing calculated
creatinine clearance, and the vast
majority of
these strokes were ischemic. So there's a
possibility that a dose reduction in
renally
impaired patients intended to decrease
bleeding may
increase the risk of stroke in those
patients at
highest risk.
We should also consider the
hepatic
findings, as will be presented by Dr.
Sheth, and we
have examined the possible relationship
between
melagatran exposure and ALT
elevations. As pointed
out in our briefing document, we have
observed an
association between increasing melagatran
exposure
and increasing ALT elevations greater
than 3 times
upper limit of normal, but this
relationship is
very weak. And as shown here, the relationship
33
between melagatran AUC and peak ALT
elevation in
individual patients, while statistically
significant, does not suggest a clear
relationship
between melagatran exposure and ALT
elevations.
In addition, we agree with the agency's
conclusion that, aside from the ALT
elevations
noted with ximelagatran, there is no
difference in
the overall adverse event profile between
ximelagatran and comparators in the
long-term
dosing study pool.
Factoring in the occurrence of
major
bleeding, stroke and systemic embolic
events, ALT
elevations, and the overall adverse event
profile,
the observation of increased plasma
melagatran
concentrations in renal impairment does not
appear
to justify a dose reduction in these
patients. We
believe our data support a fixed dose of
ximelagatran in the patient populations
studied.
Now I'd like to show the steady-state
plasma concentrations of melagatran in
atrial
fibrillation patients receiving a fixed
dose of 36
milligrams ximelagatran twice daily. There are
34
four key points here.
Plasma concentrations fluctuate
during the
dosing interval, remaining largely above
0.05
micromolar and infrequently exceeding 1
micromolar.
Mean trough melagatran
concentrations
after 36 milligrams are approximately 0.2
micromolar. So should a patient miss a dose of
ximelagatran, the 4- to 5-hour half-life
of
melagatran means that low but
pharmacologically
active concentrations remain for up to 24
hours
post-dosing. And the effect of melagatran is gone
once it is cleared from plasma by the
kidneys.
This emphasizes the importance
of
maintaining good diuresis in the
management of
bleeding.
And while there is no specific antidote,
if needed, melagatran can be dialyzed.
And, lastly, the APTT is
prolonged in
patients and may help identify a residual
anticoagulant effect.
A critical aspect of oral
anticoagulation
is maintenance of a stable effect over
time, and we
have confirmed the long-term stability of
oral
35
ximelagatran. Shown in yellow are the plasma
concentrations of melagatran in atrial
fibrillation
patients in the Phase II study, SPORTIF
II. We
remeasured plasma melagatran
concentrations in a
subset of those same patients between 13
to 16
months later in SPORTIF IV, a long-term
continuation study of SPORTIF II.
The mean plasma concentrations
of
melagatran are completely overlapping,
and the
variability in exposure within individual
patients
was low, with a coefficient of variation
of 25
percent, indicating that oral
ximelagatran results
in stable and reproducible plasma
concentrations of
melagatran with long-term repeated
dosing. This
stability enabled us to conduct our
clinical
studies using a fixed dose without
coagulation
monitoring.
So we can conclude from this
extensive
clinical pharmacology program
pharmacologically
active concentrations of melagatran are
rapidly
achieved and maintained in a broad range
of
patients.
There is also no effect of food or
36
alcohol and a low potential for drug
interactions.
The key attributes of
ximelagatran are,
therefore, its oral availability, rapid
onset of
action, low potential for drug
interactions, and
use at a fixed dose without coagulation
monitoring.
Now I'd like to introduce Dr.
Jay Horrow,
who will provide to you an evaluation of
the
efficacy of ximelagatran demonstrated in
Phase III
clinical studies.
DR. BORER: We'll just stop for one moment
to make sure there are no issues that
need to be
clarified. The relation of renal function to
melagatran exposure undoubtedly is going
to be
discussed to a greater extent later, but
I think we
should hold that until we hear from the
FDA
presentations, and then we can talk about
that.
But if there are any issues that need to
be
clarified regarding the pharmacology, we
should do
that now.
Steve?
DR. NISSEN: Two very brief questions. Is
anything known about the mechanism of
macrolide
37
interaction? Have you explored that at all?
DR. SARICH: Yes.
We were slightly
surprised to find that interaction since
we don't
interact with the P-450 system. It appears that
the interaction involves transport
proteins of some
kind, and we've looked at a range of
different
compounds that we've investigated, and it
at this
point appears isolated to the macrolide
antibiotics
we've studied.
DR. NISSEN: And the second question is:
You showed the coagulation effect during
therapy,
and I wondered if you have additional
data on what
happens in, let's say, the first 72 to 96
hours
after terminating therapy. Is there evidence of a
rebound phenomenon?
DR. SARICH: We have not observed that
pharmacologically, as far as coagulation
time
assays.
DR. NISSEN: Okay.
But that has been
studied.
DR. SARICH: We've followed out to 24
hours after single-dose administration
and not seen
38
any evidence--
DR. NISSEN: But not longer than 24 hours?
DR. SARICH: Not that I can recall.
DR. BORER: John?
DR. TEERLINK: The other question I have
is:
In terms of the relationship between the
melagatran AUC versus the peak ALT elevations,
how
was the melagatran AUC derived?
DR. SARICH: Yes, these were derived using
a population pharmacokinetic model. So the
patients that received ximelagatran in
the Phase
III clinical studies had plasma samples
collected.
Over 80 percent of the Phase III patient
population--in the long-term population
had a
plasma sample collected. Using a pharmacokinetic
model that was developed by the team, we
were able
to estimate the exposure to melagatran in
those
patients.
DR. BORER: Ron Portman?
DR. PORTMAN: Noting differences in the
chronopharmacology of drugs, were the
curves you
showed similar for both the morning and evening
39
doses?
DR. SARICH: Are you speaking about the
coagulation time assay--
DR. PORTMAN: No. I
was talking about the
plasma concentrations.
DR. SARICH: Pharmacokinetics?
DR. PORTMAN: Right, pharmacokinetics.
DR. SARICH: Yes, they are consistent
under administration during the day or
overnight.
DR. BORER: Jonathan, go ahead.
DR. SACKNER-BERNSTEIN: In the analysis
that you showed the stability of the
concentrations
of the drug over time from the SPORTIF II
and
SPORTIF IV population, did you perform
that
analysis restricting to patients who had
samples at
both times? Because the analysis you showed had a
larger population at baseline compared to
a subset
later.
DR. SARICH: Right.
We've done it both
ways.
The figure actually represents the larger
number in the SPORTIF II study and a
smaller number
in SPORTIF IV. The intra-subject variability I
40
noted was only the subjects that had
sampling at
both time occasions.
DR. BORER: Alan?
DR. HIRSCH: In the PK and AUC curves that
you've generated, were there any changes
or
differences noted based on ethnicity,
geographic
sampling of a population, or gender?
DR. SARICH: Are you asking pharmacokinetic--
DR. HIRSCH: Yes, PPK differences between
subgroups.
DR. SARICH: The main factor we've
observed between any subgroups has been
differences
in renal function, calculated creatinine
clearance.
We have not observed any significant
effects of
other demographic parameters, age,
gender, race,
BMI, body weight. It appears that exposure--the
most influential demographic factor is
calculated
creatinine clearance.
DR. BORER: Susanna?
DR. CUNNINGHAM: Did you have a sufficient
African American population to actually
know
41
anything about what the African American
area of
the curve might be or handling of the
drug?
DR. SARICH: We have performed pharmacokinetic
studies in that population. I should say
both--I'll show you some data here from a
small
study.
It's not African Americans per se, but it
was a study in Europe, in Paris, in fact,
where we
had 12 blacks, 12 Asians, and 12
Caucasians, and
found no real differences between these
groups.
If we looked at the entire
patient
population, we can see here--if we look
at--you can
see the Caucasian population here. There's over
6,000 patients. The blacks where we had
appropriate pharmacokinetic information,
were 115,
as well as Asians, and the category of
other, and
no differences between these populations.
DR. BORER: Tom?
DR. PICKERING: Do you have any data on
interaction with aspirin?
DR. SARICH: Yes, we have performed
actually two studies with aspirin. There's no
pharmacokinetic interaction with
aspirin. We see
42
an additive effect on the capillary
bleeding time,
which is somewhat expected.
DR. BORER: Beverly?
DR. LORELL: Yes, with regard to body
size, you commented on and emphasized
obesity.
What about the other end of the scale,
very small
body size? Sometimes an issue in elderly women who
might be candidates for several of these
indications.
DR. SARICH: We have less data in very
small individuals, but what we know about
that
population is that it's primarily their
calculated
creatinine clearance that influences
their
exposure.
DR. BORER: Jonathan?
DR. SACKNER-BERNSTEIN: I know we're going
to get back to the renal function
question, but
there was one set of slides you showed
where you
tried to give us some reassurance about
the
relationship between bleeding and renal
function.
And you showed the risk of bleeding as
calculated
creatinine clearance reached the low end
of the
43
spectrum.
I wonder if you performed any
sort of
retrospective power calculation on your
ability to
detect a difference in risk, in
particular in the
patients who we may be likely to see
treated with
this drug in clinical practice, those
over 70, over
75, where calculated creatinine
clearances often
are in the 40s. So do you have an analysis there
between 30 and 50 with conditional power
to
actually detect a difference in bleeding
risk
there.
DR. SARICH: I think we could probably
best address that after the
presentations. We do
have data there, and rather than getting
into that
discussion, if the Chair would agree, we
could
address that, bring an answer to you for
that.
DR. BORER: Is that okay, Jonathan?
DR. SACKNER-BERNSTEIN: Yes.
DR. BORER: Okay.
Thank you.
T1B DR. HORROW: Ladies and
gentlemen, I'm Dr. Jay Horrow from
AstraZeneca. We
will now present Phase III data
demonstrating that
44
ximelagatran is an effective oral
anticoagulant.
In the first indication,
long-term
secondary prevention of venous
thromboembolism, we
will show ximelagatran superior to
placebo. In the
second indication, prevention of VTE
after total
knee replacement, ximelagatran was
superior to
well-controlled anticoagulation with
warfarin. And
in the chronic prevention of stroke,
ximelagatran
was noninferior to warfarin.
These indications represent a
broad range
of patient populations. We'll begin with the first
one:
secondary prevention of VTE.
Evidence has been accumulating
that
patients with acute VTE benefit from prolonged
anticoagulation after acute
treatment. The THRIVE
III trial comparing ximelagatran to
placebo
contributes to this growing body of
evidence.
Randomized patients had an acute symptomatic
VTE
objectively confirmed and had completed 6
months of
treatment without VTE recurrence, also
objectively
documented at randomization. Anticoagulation was
desirable but not essential for these
patients,
45
that is, they had idiopathic VTE or
probable
hypercoagulable conditions. Health status had to
be compatible with survival for an
additional 18
months.
In THRIVE III, 1,223 patients
receives in
double-blind fashion either oral
ximelagatran 24
milligrams twice daily or placebo for up
to 18
months.
Selection of 24 milligrams for this trial
came from a consideration of preclinical data
and
data from Phase II trials in the
orthopedic surgery
indication. These PK data from a Phase II European
trial in patients undergoing hip or knee
replacement demonstrate that
administration of 8
milligrams ximelagatran twice daily, the
lowest
curve, achieves plasma melagatran
concentrations of
about 0.05 micromolar. This is the level at which
anticoagulant activity with melagatran
begins based
on the data previously shown by Dr.
Sarich.
Progressively higher doses of
oral
ximelagatran, 12, 18, and 24 milligrams,
achieved
higher melagatran concentrations, more
anticoagulant
activity, and more time above the 0.05
46
micromolar threshold for each dose.
Outcome data from that same
orthopedic
surgery trial suggest that 24 milligrams
is the
most promising dose for efficacy. The 24-milligram
dose also had a reassuring bleeding
profile. We
chose 24 milligrams for THRIVE III with
placebo
comparator without establishing
dose-limiting
toxicity, in this case bleeding. The choice was an
informed judgment taking into consideration,
first,
the need for efficacy demonstrated by the
benefits
seen here in joint replacement, an
intense
thrombotic stimulus; and, second, the
need to avoid
excess bleeding because the standard of
care is no
anticoagulant therapy at all.
The trial compared ximelagatran
to placebo
in the rate of recurrence of symptomatic,
objectively confirmed VTE. VTE encompasses both
deep vein thrombosis, DVT, and pulmonary
embolism,
PE, because PE originates from a thrombus
in the
systemic venous circulation, whether
overt or not.
The primary endpoint compared
ximelagatran
to placebo using a time-to-event
analysis. A
47
recurrence of VTE required signs or
symptoms of
VTE, that is, a clinical event, and
subsequent
objective confirmation. A blinded independent
endpoint committee evaluated and
adjudicated all
clinical endpoints, including major
bleeding
events.
The ximelagatran- and
placebo-treated
cohorts displayed similar demographic
profiles. As
indicated by creatinine clearance between
30 and
80, 23 percent had some degree of renal
impairment.
The index VTE event was or included
pulmonary
embolism for more than one-third of
patients. This
Kaplan-Meier curve shows the cumulative
incidence
of the primary outcome in the
ximelagatran and
placebo groups, analyzed by intention to
treat.
Seventy-one patients in the placebo group
suffered
recurrent VTE, including 23 PEs, for a
cumulative
rate of 12.6 percent, while only 12
patients in the
ximelagatran group had recurrent VTE,
including
only two PEs, for a cumulative rate of
2.8 percent.
The 9.8-percent difference, significant
at p less
than 0.0001 by log rang test indicates
that one VTE
48
recurrence is prevented by ximelagatran
treatment
for up to 18 months to 10 patients. The associated
hazard ratio, 0.16, indicates a risk
reduction of
84 percent by ximelagatran relative to
placebo.
The composite endpoint of total VTE
included both DVT and PE. Benefit of ximelagatran
over placebo occurred for each component
of this
composite endpoint--clinical DVT,
clinical PE, and
their combination.
The superiority of ximelagatran
to placebo
is robust to multiple, prespecified
sensitivity
analyses listed here. Each comparison demonstrated
a significance level less than 0.0001
Here we examine efficacy in
subpopulations. Small
diamonds depict point estimates of
the odds ratios of ximelagatran to
placebo, and
horizontal bars show their 95-percent
confidence
intervals. Superiority of ximelagatran over
placebo remains in all subgroups strata
of
reasonable size.
In THRIVE III, the oral
thrombin inhibitor
ximelagatran, 24 milligrams twice daily
for up to
49
18 months, effectively reduced the number
of
recurrent VTE events following 6 months'
treatment
of an acute VTE. The results are robust and
consistent across multiple endpoints and
subgroups
and demonstrate a clinically relevant
benefit.
The second indication under review today
is the prevention of VTE in patients
undergoing
knee replacement surgery. Major joint replacement
surgery challenges any anticoagulant to
prevent VTE
without counteracting surgical hemostasis. VTE
prevention contributes heavily to the
benefit/risk
balance for joint replacement surgery.
The current options to reduce
the
occurrence of VTE after total knee
replacement
include the injectable agents
low-molecular-weight
heparin and fondaparinux and oral
warfarin. One
FDA comment regards the choice of
warfarin as the
comparator for these trials.
We chose warfarin for several
reasons:
First, it is the agent most
commonly used
for this purpose in North America, and we
administered warfarin, as orthopedic
surgeons do,
50
beginning the night of surgery.
Second, warfarin, like
low-molecular-weight heparin, is a Grade
1A
recommended therapy for this purpose,
according to
current American College of Chest
Physicians
Consensus Conference Guidelines.
And, third, warfarin is
associated with
less bleeding than the injectable
anticoagulants
and so is a more daunting comparator for
ximelagatran in terms of surgical
hemostasis.
Two independent double-blind
Phase III
trials--EXULT A and EXULT B--enrolled
patients
undergoing primary elective total knee
replacement.
EXULT A studied 24 and 36 milligrams
ximelagatran
and warfarin. We had studied 24 milligrams in this
context previously and found protection
similar to
but not better than warfarin at p equal
0.07. We
found that result surprising. Unsure whether or
not it was a Type II error, we designed
EXULT A
with two ximelagatran arms: one using 24
milligrams and the other using 36
milligrams.
Warfarin and its paired placebo
began, as
51
typically practiced in the U.S., the
evening of the
day of surgery while ximelagatran and its
placebo
began early on the morning after the day
of
surgery.
Treatment continued for 7 to 12 days,
after which all patients underwent
bilateral
venography.
Based on the results of EXULT
A, EXULT B
studied only 36 milligrams ximelagatran
and
warfarin.
Warfarin was aggressively and
successfully dosed to drive the INR
rapidly to its
target of 2.5, with an accepted range of
1.8 to
3.0.
The primary outcome formed the composite of
distal and proximal DVT by venogram
performed
between days 7 and 12, objectively
confirmed
symptomatic DVT or pulmonary embolism up
to 2 days
after venography, and all-cause mortality
up to 2
days after venography. Both trials utilized the
same blinded independent committee for
event
adjudication.
The treatment groups in the
EXULT trials
were balanced and represented well the
population
of patients in the United States
undergoing total
52
knee replacement. More than a third of the cohort
displayed some degree of renal
impairment.
Here are the primary results
for EXULT A
and EXULT B. In EXULT A, ximelagatran 36
milligrams, in yellow, showed superiority
to
well-controlled anticoagulation with
warfarin, in
gray, at p equals 0.003. EXULT B confirmed those
results, with p less than 10
-5. These results yield
relative risk reductions of 26 and 29
percent and
numbers needed to treat of 14 and 11,
respectively.
In EXULT A, ximelagatran 24
milligrams, in
orange, and warfarin, in gray, did not
differ, with
event rates of 24.9 and 27.6 percent,
respectively.
That p value is 0.28.
The delay in anticoagulation
with warfarin
administration suggests that it may act
like a
placebo in EXULT. In fact, warfarin rates, in
gray, are the lowest ever obtained in
knee
replacement clinical trials with
warfarin, perhaps
because of the rapid achievement in EXULT
of
therapeutic INRs. Placebo rates are historically
over 60 percent, and the mean INR in
EXULT was 2.4
53
on post-op day 3. The warfarin group provided a
formidable comparator for ximelagatran in
the EXULT
studies.
Here we see results for the
components of
the composite primary endpoint. As expected, the
majority of events occurred in the distal
leg.
Rates for proximal DVT, for PE, and for
death were
low in all treatment groups. Another point raised
by FDA is how clinically relevant distal
DVT is as
a component of that endpoint. It's important to
note that 10 to 20 percent of distal
thrombi extend
to become proximal thrombi, and either
one can
cause pulmonary embolism, making all
three
phenomena clinically relevant components
of a
composite endpoint. In fact, proximal and distal
deep vein thrombosis detected by
venography,
whether symptomatic or not, is a primary
endpoint
historically accepted by the agency for
VTE
prophylaxis registration trials.
This display of the primary
outcome by
subgroup strata shows differences in
event
incidences between the pooled
36-milligram
54
ximelagatran and pooled warfarin
groups. These
results, with small numbers in just a few
subgroups, reveal no discrepancies in
efficacy in
any particular subpopulation.
Oral ximelagatran, 36
milligrams, provided
superior protection against VTE and
all-cause
mortality compared with well-controlled
anticoagulation with adjusted-dose
warfarin, a
clinically relevant comparator. This superior
protection was consistent across multiple
subgroups. These data support the efficacy of
ximelagatran for the indication
requested.
The third indication considered
today is
the protection of patients from stroke
and other
thromboembolic complications of atrial
fibrillation. We have demonstrated that
ximelagatran provides this protection, as
well as
does warfarin, across a broadly based
patient
population.
Two independent pivotal
trials--SPORTIF
III, dosed, open-label in 23 countries in
Europe
and Asia, and SPORTIF V, conducted
double-blind in
55
North America--enrolled patients eligible
for
warfarin therapy according to existing
treatment
guidelines, that is, those with
nonvalvular atrial
fibrillation with at least one additional
risk
factor for stroke. Each SPORTIF trial by itself
studied more patients than all previous
trials of
stroke prevention in atrial fibrillation
combined.
Each trial compared 36 milligrams twice
daily
ximelagatran to dose-adjusted warfarin in
preventing all strokes and systemic
embolism, hard
clinical endpoints in an
intention-to-treat
fashion.
The choice of 36 milligrams
came from
several considerations. There is no surrogate
marker for stroke and systemic embolism,
and both
events are devastating. Thus, we performed a
dose-ranging study for safety and
tolerability of
ximelagatran 20, 40, and 60 milligrams in
SPORTIF
II, a 3-month Phase II atrial
fibrillation study.
While the numbers were small in that
study,
bleeding was most frequent with 60
milligrams and
also the warfarin comparator, and less
frequent
56
with 20 or 40 milligrams
ximelagatran. We knew
that 24 milligrams was effective in the
Phase II
European orthopedic surgery program and
reasoned
that any downside impact of potential
additional
strokes with 24 milligrams would be far
worse than
the bleeding seen with 36 milligrams in
this
nonsurgical context. Using this educated judgment,
we chose 36 milligrams in the Phase III
atrial
fibrillation program.
Let's take a moment to consider
the
open-label nature of the SPORTIF III
trial. The
majority of prior stroke prevention
trials in
atrial fibrillation also utilized an
open-label
format based on the difficulty of
managing
anticoagulation in blinded fashion. SPORTIF III
featured open-label dosing at sites, but
also
centrally randomized allocation and two
additional
levels of blinding: blinded local assessment of
primary endpoints by study-affiliated
neurologists,
and blinded independent central committee
adjudication of all study endpoints. SPORTIF V
featured double-blind, double-dummy
medication, and
57
for patients receiving ximelagatran and
placebo
warfarin, sham INR values that mimicked
those
obtained during warfarin therapy.
The established efficacy of
warfarin
precluded a placebo comparison. Because warfarin
is so efficacious, it is reasonable to
establish
ximelagatran efficacy in comparison to
warfarin,
and we did so using a noninferiority
design. In
consultation with an executive steering
committee
and data safety monitoring board compose
of leaders
of prior stroke prevention trials and a
statistician expert in noninferiority
trials, we
prespecified a 2-percent per year
absolute
noninferiority margin. The choice of this margin
has been questioned. The choice of 2 percent arose
partly from an expected 3.1 percent
warfarin rate,
but more importantly, from consideration
of the
clinically tolerable absolute difference
in stroke
rates considering warfarin's overall
clinical
profile.
A similar consideration drove designers
of the SPAF III trial to power that trial
to detect
a 2-percent per year event rate with
upper
58
confidence bounds of 3 for a population
at lower
risk of stroke. Even so, we prespecified a more
conservative 2-percent upper confidence
limit. The
point estimate of the difference in event
rates
needs to be much smaller than 2 percent
for the
worst case, that is, the upper confidence
limit, to
be less than 2.
The strength of the 2-percent
per year
absolute margin resides in its clinical
relevance,
its prespecification, and that it is
conservative.
At screening, those patients already
taking oral anticoagulants interrupted
that therapy
to decrease INR to 2 or less by the time
of
randomization, at which time patients
received
either warfarin or ximelagatran. Each trial
achieved a degree of warfarin control
rarely found
in routine clinical practice. The warfarin-treated
groups constituted formidable comparators
for
ximelagatran, particularly in SPORTIF
V. Samsa and
colleagues found that most patients
taking warfarin
spend more than half the time on
treatment outside
the therapeutic range. In SPORTIF V, only 15
59
percent of patients did so.
The ximelagatran- and warfarin-treated
cohorts displayed nearly identical
demographic
profiles in each independent Phase III
trial, seen
here as pooled data. Patients reflected well the
elderly population of nonvalvular atrial
fibrillation patients requiring
anticoagulation for
stroke prophylaxis, and the majority had
impaired
renal function.
In SPORTIF III, warfarin, shown
in gray,
displayed an event rate of 2.3 percent
per year
compared to 1.6 percent per year with
ximelagatran,
shown in yellow.
In SPORTIF V, the rates were
1.2 for
warfarin, in gray, and 1.6 for
ximelagatran, in
yellow.
Primary event rates with
ximelagatran are
nearly identical in SPORTIF III and
SPORTIF V. For
warfarin, the rates fall within the range
of event
rates in previous trials, 0.6 to 4.1
percent per
year.
For comparison, the pooled rate
in prior
60
stroke trials for patients in this risk
category
taking placebo or aspirin was over 8
percent per
year.
The difference in event rates in SPORTIF
III, 0.66, favoring ximelagatran, had an
upper
confidence limit of 0.13, less than the
prespecified 2-percent margin. In SPORTIF V, the
difference of 0.5 favoring warfarin had
an upper
bound of 1.03, also less than the
prespecified
2-percent per year margin. Thus, each trial
independently succeeded by satisfying the
prespecified noninferiority criterion for
the
primary outcome.
As expected, most of the events
in this
composite outcome were ischemic strokes.
Hemorrhagic stroke and systemic embolism
occurred
more rarely and did not influence the
primary
endpoint substantially.
Several sensitivity analyses
confirmed the
results of the primary analysis. One such
analysis, depicted here, included
all-cause
mortality in the primary endpoint at the
suggestion
of the agency. SPORTIF III returned event rates of
61
4.2 and 5.1 for a difference of 0.87
favoring
ximelagatran, while SPORTIF V rates were
nearly
identical at 4.7 and 4.8.
Adding all-cause mortality
shifted each
study's event rate difference point
estimate to the
left in favor of ximelagatran.
Another sensitivity analysis,
depicted
here, used an on-treatment approach using
the same
endpoints and the same population, but
not counting
events that occurred after stopping study
treatment
for 30 continuous or 60 total days. The upper
bound of negative 0.18 indicates
superiority in
SPORTIF III. The value of 1.2 in SPORTIF V
indicates noninferiority to
well-controlled
warfarin.
For each trial, we also performed a
paper
comparison of ximelagatran to placebo by
factoring
in the results of the six prior stroke
prevention
trials.
We obtained original data from those
trials to utilize the same endpoint
events as in
SPORTIF.
Demographics of patients in these trials
were similar to those of SPORTIF
patients.
62
In these calculations, SPORTIF
III and
SPORTIF V separately demonstrated
statistically
significant risk reductions for
ximelagatran
relative to putative placebo, as did the
pooled
SPORTIF data. Ximelagatran works as an
anticoagulant in this population.
As before, here we see differences in
primary event rates according to
demographic
subgroups. These pooled results reveal no
discrepancies in any particular
subpopulation,
including the elderly, women, the obese,
and those
with poor renal function.
In conclusion, for atrial
fibrillation
each of two trials independently met its
objective,
demonstrating that 36 milligrams of
ximelagatran
taken twice daily prevented stroke and systemic
embolism to an extent similar to that of
well-controlled anticoagulation with
warfarin.
For long-term secondary VTE
prevention,
the THRIVE III trial demonstrated that 24
milligrams ximelagatran twice daily
prevented VTE
recurrence compared to placebo.
63
And in total knee replacement
surgery, the
two independent EXULT trials showed that
36
milligrams twice daily prevented VTE and
all-cause
mortality better than dose-adjusted
warfarin.
Based on five pivotal trial,
each the
largest in its field, involving more than
12,000
patients, these data establish the
effectiveness of
ximelagatran as an oral anticoagulant in
a variety
of patient populations at high risk for
thromboembolism.
Dr. Sunita Sheth will next
address
particular safety aspects of
administration of
ximelagatran for these indications.
DR. BORER: Thank you very much, Jay.
Again, we'll take a minute to
see if
anyone has any issues that require
clarification.
Clearly, we are going to talk about or
probably
we're going to be talking about the selection
of
the delta for the noninferiority trial,
but I don't
want to get into that discussion
now. We have some
extraordinary statistical fire power here
between
Tom on the committee and Lloyd Fisher and
Jerry
64
Faich sitting over there and the FDA
statisticians.
I think we'll wait on that until after
all the
presentations, including the FDA
presentations,
have been made. But if we have any issues of fact
that need to be clarified now, let's do
it.
Jonathan?
DR. SACKNER-BERNSTEIN: In the FDA
briefing document, it points out that
there were
patients who were withdrawn from the study for
whom
there is not information about whether
they
underwent or suffered any events. If that's
correct, please clarify, because it looks
as though
from the study flow that that means in
SPORTIF V as
many as 15 percent of the patients we
basically
would not have any clinical outcomes data
available
from the point in time when they
withdrew. Is that
correct?
DR. HORROW: We followed up on all of our
patients in the SPORTIF III and V trials
to the
greatest extent possible, and, in fact,
after we
were done with our follow-up, at the time
of final
closure, locking the database, we were
left, out of
65
7,922 patients, with only 63 patients
about whom we
were unsure of their final status.
DR. SACKNER-BERNSTEIN: So that would mean
that the FDA briefing document is incorrect,
because the FDA briefing document states
that--and
I'm looking at page 36 of the clinical
review from
Cardio/Renal Division. It says in the first
paragraph that patients that were
discontinued from
study medication and withdrew from study
were not
followed for primary efficacy endpoints
or death.
And then as you turn to page 45 with the
patient
disposition in SPORTIF V, it looks as
though
there's 300 study withdrawals from the
ximelagatran
group and 286 from the warfarin
group. So that
means that about 15 percent would have
incomplete
clinical outcomes data, but you're saying
there's
only 63.
So could you explain for us
where the
disparity should be settled?
DR. HORROW: It is conceivable that there
is a misinterpretation of the term
"study drug
discontinuation" and
"withdrawal from study." More
66
likely, the misunderstanding may accrue
from the
follow-up efforts that we made to
ascertain the
vital status of every patient in the
SPORTIF
trials.
We followed up on every
patient, aside
from the 63 that I just mentioned, and
are
confident in their vital status, knowing
whether
they were alive or dead, whether they had
a stroke
or not, in our database.
DR. FLEMING: Could I just clarify? So I
assume what you then did is you defined a
date of
data lock or closure where on that
calendar date
you wanted to follow all patients
relative to their
survival status and stroke status. Are you saying
then for all but 63 patients you knew
their
survival status and stroke status as of
that
calendar date for data lock?
DR. HORROW: Exactly, and that would be
the data lock date for each respective
trial--SPORTIF III and SPORTIF V. That is correct.
DR. BORER: Steve?
DR. NISSEN: I want to make sure I
67
understand how you maintained the blind,
particularly in SPORTIF III. Obviously with
warfarin, you may require frequent dose
adjustments
and so on. So in the open-label, particularly
SPORTIF III, how did you maintain--in
both trials,
I'd like to understand the procedures
that were
undertaken. I guess in the open-label trial there
was no blinding, right? The physicians and
patients knew what they were receiving;
is that
correct?
DR. HORROW: In the open-label trial?
DR. NISSEN: Yes.
DR. HORROW: It was open-label dosing, and
so you are correct that the physicians
and the
patients knew the drug, and the
evaluators, the
neurologists locally, and the central
adjudication
committee were blinded and didn't know.
DR. NISSEN: Okay, I understand. And
SPORTIF V, then, how did you adjust
warfarin and
maintain the blind? Explain to me how that was
done.
DR. HORROW: It was quite tricky and
68
involved quite a bit of work on the basis
of the
investigators and quite a burden for the
patients.
In SPORTIF V, all of the INR values were
obtained
in almost all cases by only two
laboratories--that's an incredible degree
of
standardization for
thromboplastin--either the
centralized laboratory or a point-of-care
machine
that had standardized cards.
In each case--well, for the point-of-care
machine, a coded number was produced by
the
machine.
That was called in to a central
randomization area, and that service then
faxed to
the site either the true INR value if the
patient
was really in the warfarin group or a
shammed INR
value if the patient was truly taking
ximelagatran.
So the site was unaware when it received
the fax
what group the patient was in.
If the test was done at the
centralized
laboratory, then the centralized
laboratory
likewise sent the results to the IBRS
site, the
specialized service, which then, again,
faxed
either the shammed or the true INR value
to the
69
site.
DR. NISSEN: And then dose adjustments,
how were those then made? I mean, obviously some
of the patients needed a dose adjustment,
so what
happened then?
DR. HORROW: Well, as you know, for
ximelagatran or its placebo there were no
dose
adjustments. But for warfarin or its placebo, each
investigator adjusted the dose based on
their usual
practice considering the patient and the
INR value
or shammed value--they didn't know which
it
was--they'd received by fax.
DR. NISSEN: So there was no--it was all
done per local physician practice. There was no
standard applied to how dose adjustments
were made.
Is that right?
DR. HORROW: That's correct. We did not
require all the investigators to adjust
their
patients' warfarin doses against some
standard.
This was to be a very real-world--as much
as we
could--type of adjustment in terms of
warfarin or
shammed dosing.
70
DR. NISSEN: And I assume the reason you
didn't do that in SPORTIF III was that
you just
felt it was too difficult.
DR. HORROW: In SPORTIF III, the
investigators were very uncomfortable
with blinded
anticoagulation testing and were
unwilling to move
forward in that regard.
In SPORTIF V, our North
American
investigators embraced the randomization
somewhat
more willingly.
DR. NISSEN: So you tried to do SPORTIF
III blinded but they wouldn't go along
with it? I
don't understand exactly what happened.
DR. HORROW: It was not possible
to get
the investigators in SPORTIF III to move
forward
with the blinded testing and
anticoagulation.
DR. NISSEN: You attempted it, and then
they weren't able to comply. Is that what
happened?
DR. HORROW: At an investigators meeting,
there was--
DR. NISSEN: A rebellion.
71
DR. HORROW: There was no support.
DR. BORER: Okay.
Bill? And then we have
Tom and Alan and John.
DR. HIATT: A comment and a question. In
the knee replacement studies, you
commented that
you achieved a rapid increase in INR and
that it
was 2.4 at day 3. And I just want to comment that,
you know, there's an association between
antithrombotic and anticoagulant effects
of
warfarin.
It takes 4 to 6 days for Factor II to be
depleted, so that's a false sense of
security
around the measurement of the INR. They're still
not antithrombotic.
So my question is: If you take the
three-quarters of patients at the end of
that study
who were, quote, therapeutic versus the
one-quarter
that were not, did you look at a subgroup
analysis
around difference in VTE rates at the end
of that
time?
Were the patients who were, in fact,
therapeutic by that number equivalent in
terms of
VTE rates compared with the patients who
were
sub-therapeutic?
72
DR. HORROW: My understanding of the
question is did we perform a subgroup
analysis near
the end of the treatment interval
regarding
patients--or based on the actual INRs of
the
patients.
We do not have that analysis.
DR. HIATT: I think the speculation would
be that the differences would be erased
in those
who were therapeutic, and a major
difference
between treatments would have been in
those who
were sub-therapeutic. That was my question.
DR. HORROW: This is quite possible, and
it's important to understand that the
EXULT trials
mimicked warfarin administration in the
orthopedic
surgery realm as it is currently
practiced today in
the United States. And so it was a very relevant
way to look at the effects.
DR. BORER: Tom?
DR. PICKERING: Can you tell us how the
INR control rates in the SPORTIF trials
compared
with the same rates in the six
warfarin-versus-placebo trials?
DR. HORROW: The INR rates in the six
73
index trials had somewhat of a spread, as
would be
expected, and it's actually possible to
see that as
the INR rates are better in some of those
trials,
so are the results in terms of the
decrease in the
warfarin event rate. And our results for INR
control were really quite in the middle,
2.5,
2.4--could we have the previous slide,
please? I
can show you some data on them.
This would be for SPORTIF V,
summary
statistics. Please note in the middle column
labeled ximelagatran, we are looking at
shammed
values, and you will note that we have
2.5 at 3
months for ximelagatran and 2.4 for
warfarin, at 12
months similarly, at 24 months
similarly--right in
the middle of the desired interval. And, of
course, the other thing that you might
note here is
that there is a threshold of 4.0 for the
shammed
values to ensure that no shammed value ended
up
putting a patient unnecessarily in the
hospital
because of an elevated shammed INR.
Nevertheless, as you can see by
the ranges
here, it's quite clear that the
investigators would
74
be unable to determine whether a patient
were in
one group or the other.
DR. PICKERING: That really wasn't my
question.
I was asking if there are comparable
data for the six warfarin placebo trials.
DR. HORROW: I don't have those data
available to show you at this time.
DR. BORER: I think they're in one of our
two books, Tom.
DR. HORROW: I believe they may be in the
briefing document.
DR. BORER: If I remember correctly, they
do show a fairly wide range, as you might
expect,
but we can get those data.
Okay. Alan?
DR. HIRSCH: I have two questions. One is
to follow up Steve's question regarding
the SPORTIF
III blinding. I just always believe it's terribly
important to have blinding as a component
of major
pivotal trials, acknowledging that lack
of blind
can really alter outcomes in unexpected
ways. So I
want to just run this through one more
time.
75
Pitying the investigators that
would not
go along with your request, the patients
knew their
study assignment, correct?
DR. HORROW: In SPORTIF III.
DR. HIRSCH: In SPORTIF III.
DR. HORROW: That's correct.
DR. HIRSCH: The physicians--
DR. HORROW: The patients knew their
assignment, as did the principal
investigators.
DR. HIRSCH: And coordinators.
DR. HORROW: That's correct.
DR. HIRSCH: So how would we have any
confidence that the adjudicating
neurologist would
have any blind maintained at all?
DR. HORROW: Well--
DR. HIRSCH: I worry.
DR. HORROW: Your point is well taken that
that cannot be assured with
certainty. We can say
that there were efforts made to make sure
that the
neurologist was not told on purpose the
assignment
of the patient, and we know also that all
members
of
the central adjudication committee, which
76
evaluated all the endpoint events upon
which the
results are based, did so in a totally
blinded
fashion.
DR. HIRSCH: I guess if there was
concordance between those two groups, I'm
somewhat
satisfied.
Let me come back with a
follow-up question
for EXULT, if I could. The data that we have
demonstrates benefits of ximelagatran
versus
Coumadin preventing DVT in this
population at risk
after total knee replacement. And as we'll discuss
later, most of that data is regarding
distal DVT,
which I do care about. But in the database, do we
have any evidence, quality-of-life
measurements,
girths, anything that demonstrates a
clinically
relevant effect for the patient? In other words,
in the absence of venographic
surveillance, would
the patient know there was a difference
in outcome?
DR. HORROW: I'd like to ask Dr. Scott
Berkowitz, who is the medical director
for that
particular trial, to address that
issue. Dr.
Berkowitz?
77
DR. BERKOWITZ: Hi.
Scott Berkowitz,
AstraZeneca. There was not any type of
quality-of-life assessment in this
short-term
trial.
The symptomatic events were collected as
well, including distal, proximal, and
PEs. They
were low, as they are in TKR trials and
did not see
a difference, a statistical difference.
DR. BORER: There was a question I was
going to hold until the end, but it seems
to be
relevant right here in view of Alan's point. You
probably have a back-up slide, and Alan
just
suggested that he probably has the data
off the top
of his head. But can you tell us, among people
historically from older trials where data
would be
available who have asymptomatic distal
DVT and who
aren't treated, what's the risk of
subsequent
thromboembolic events during some
follow-up period?
DR. BERKOWITZ: Well, we don't have the
greatest data on that, unfortunately, in the
literature. What we know is that 10 to 20 percent,
depending on what you're readings--there
are only
three or four studies--do propagate from
distal to
78
proximal.
We know about 5 percent propagate to PE.
We don't know the actual recurrence rate
of what
further DVTs would be after, say, 6
months. We do
also know that post-thrombotic syndrome
occurs in 5
percent of patients in 2 to 7 years after
total
knee replacement. Those are the real data that we
have.
Not an area well studied.
DR. BORER: Jonathan, and then Steve.
DR. SACKNER-BERNSTEIN: I noticed that in
the trials for the study flow of patients
in
several of your trials, including THRIVE,
both
EXULTs, and SPORTIF V, that there is a
number of
patients listed as being enrolled and
then a second
number of patients listed as being
randomized. And
there's very little information in either
the FDA
or the sponsor's documents about what
happened to
those patients. So I'm wondering if you could
describe it because in each of the cases
you're
looking at probably in the range of 10
percent of
the patients who are enrolled that don't
make it to
randomization.
DR. BERKOWITZ: Maybe I'll first try to
79
answer for the EXULT and THRIVE, and then
ask Dr.
Horrow for atrial fibrillation.
For the EXULT trials, patients
were
enrolled, meaning that they were seen as
an
outpatient up to a month before the
procedure, and
then would come into the hospital, and if
they had
the surgery of interest, which was
primary total
knee replacement, then would be
randomized,
assuming they went through the
eligibility
criteria.
The most common reason patients wouldn't
go from enrollment to randomization is
that either
the--there were two: one, that the surgery was
cancelled, and then the patient wasn't
rescheduled
for the procedure--excuse me, for the
study, but
did do the procedure; the other was that
with these
trials rapidly enrolling, we had many
people lined
up but then the study--we reached our
enrollment.
Those were the two major causes.
For the THRIVE study, these
were patients
who had acute events for 6 months treated
acute DVT
and then went on to a 6-month--either
placebo or to
ximelagatran 24-milligram arm, and most
of these in
80
terms of just taking a look here--I can
just show
you what we've got in terms of that. In terms of
the ones that were not randomized, there
were 123
of those patients, and most of this
turned out to
be eligibility not fulfilled or withdrawn
consent.
And that is a common thing that patients
might
think more about the study if they want
to
participate in such a long-term--and then
I could
turn it over to Dr. Horrow.
DR. HORROW: In the SPORTIF trials, the
major reason why patients were enrolled
but not
randomized was because of the failure of
an
eligibility criterion; in particular, the
major one
was the ability to achieve two electrocardiograms
demonstrating atrial fibrillation in the
manner
specified. And as a result, the principal
investigators did not enroll a number of
the
patients whom they at first thought were
good
candidates.
DR. SACKNER-BERNSTEIN: Can I just follow
up?
One quick point in follow-up. In
the patients
enrolled in SPORTIF where many of them
were coming
81
off the vitamin K antagonist, how
many--even if it
was a minority, how many of those
patients had some
sort of clinical event that led them not
to be
randomized?
DR. HORROW: I understand your interest is
in seeing what happens to the patients
who came off
of vitamin K antagonist in the enrollment
period,
did they happen to have events. I believe that we
have some data on that, although I can't
say for
sure that all of these did not
enroll. They may
have had an event after enrollment. If you'll just
give me a moment, I'll see if we can find
these
data.
Yes, thank you. Here we see the number of
patients with primary events who had an
event
within 30 days of discontinuing study
drug, and
this would be either the ximelagatran or
the
warfarin group. And this would be during the
course of the trial. As you can see, there's not
much difference between the two groups.
I think this may address the question
that
you're getting at, which is what happens
when
82
patients discontinue their anticoagulant.
DR. SACKNER-BERNSTEIN: Well, actually, I
find that reassuring, that information,
but really
what I was getting at was the impact of
the
strategy that would be proposed based on
the study,
which is you have a patient who's on
long-term
warfarin and you're going to convert them
potentially to a new agent. There's a period that
would be followed where there's a
transition, and
I'd like to know if that transition
period is a
period that could be associated with risk
as well.
DR. HORROW: I understand better. Thank
you.
Here are some data from SPORTIF III looking
at primary events within 7 days of
randomization.
There were three patients who had a
primary event
in the SPORTIF III trial within 7 days of
randomization, and, of course, the
patients taking
VKA--all patients had to stop their VKA
in order to
begin randomization. And there were two events in
the warfarin group and one in the ximelagatran
group.
DR. BORER: Steve?
83
DR. NISSEN: I want to come back to the
blinding issue again, and we've been
dancing around
it so let me just come to the point.
Something extraordinary
happened in
SPORTIF III and SPORTIF V. In SPORTIF III, I
calculate a hazard ratio of 1.39, 1.40
that's in
favor of ximelagatran. And in SPORTIF V, the
hazard ratio is 1.35 in favor of
warfarin. And so
you have almost a completely opposite
effect on the
point estimates, which, you know, is
really unusual
when you consider the similarity of the
trials.
So we're al trying--we're all
sitting here
looking at the briefing document, and
we're trying
to figure out what could possibly have
happened
here so that, you know--I mean, there's
essentially
a 39-percent greater risk for warfarin in
SPORTIF
III and a 39-percent greater risk for
ximelagatran
in SPORTIF V. And the only big difference in the
two trials is that one was blinded and
one wasn't.
And so most rational people who
look at
that would say, well, we're going to
believe the
blinded results, we're not going to
believe the
84
unblinded results. And so this is a real
credibility issue, and I think we might
as well
just put it on the table and get your
reaction to
it.
DR. HORROW: In fact, there are many
differences between SPORTIF III and
SPORTIF V that
are confounded with the open-label and
double-blind
nature of those two trials. The first and foremost
is geography, namely, that one study was
conducted
in Europe and Asia and the other in North
America,
and practice issues may pertain.
Secondly, although SPORTIF V
patients more
often had hypertension, their blood
pressures were
6 mm mercury lower, on average, than
patients in
SPORTIF III.
And, third, there was an
artificially
intense control of INRs in SPORTIF V
relative to
SPORTIF III, because in SPORTIF III there were
over
270 clinical laboratories conducting INR
measurements, but there were essentially
two in
SPORTIF V, achieving some kind of
standardization
that is difficult to quantify.
85
Another aspect that is
important to
consider is that the ximelagatran rates
were
identical in the two trials. And in the warfarin
trials--I'm sorry, in the two trials, the
ximelagatran rates were identical, about
1.6. The
warfarin rates appear disparate. But those rates
are actually within the range of rates
that are
seen in prior stroke prevention trials.
What we may be looking at here
is another
manifestation of the variability of
warfarin. This
slide shows in yellow the warfarin rates
from the
six index trials, in orange the two rates
from the
SPORTIF trials, and in dark brown the
meta analysis
rate for the trials in yellow. And as you can see,
the SPORTIF rates are within the range of
the
warfarin rates from the previous trials.
I hope that gives some
perspective.
DR. FLEMING: Could you put that slide up
again?
Can I follow up?
DR. BORER: Sure.
Let me just put some
ground rules here, though. Steve has highlighted
what will be one of the key issues for
discussion
86
later on, and rather than get into it in
great
detail here and get bogged down for the
next hour,
perhaps we can deal only with issues of
fact, and
then we'll get into the evaluation of
those facts a
little bit later.
But with that in mind, go
ahead, Tom.
DR. FLEMING: If you could put that slide
up, I just think for clarification, I
don't think
that the point you just raised really
answered
Steve's question. Steve's question had more to do
with the heterogeneity in the relative
risk
estimate across to pivotal studies. This is
getting at the heterogeneity of the
control arm
event rates across trials. And, in fact, those are
different phenomenon. This really gets at the
unreliability of noninferiority
comparisons because
of this tremendous heterogeneity, which
is a
separate issue.
While I have the mike, could I
ask a
question that I had in mind? That is, one of the
things that's always concerned me in
trials with
venograms is that we end up with a lot of
missing
87
data, far more than what this committee
would be
used to accepting in a manner to maintain
integrity
of randomization. I think you had 20 and 15
percent, respectively, missing the
outcome
assessments in EXULT A and EXULT B.
With that in mind, and also
wanting to
really focus on what are not surrogates
but true
clinical endpoints, endpoints that
reflect tangible
benefit to patients, I struggle to look
for what
are those measures that are really
tangible that
are measured uniformly in patients. Could you show
Slide CE-19 as we look at EXULT A and
B? Two of
these measures are pulmonary embolism and
death
that should be assessed, I'm assuming,
and
available in all patients. Your survival figures
here reflect, if I pool here, five deaths
against
three.
The agency on page 26 of their briefing
document has ten against four, so you're
missing
five deaths in the Exanta arm and one in
the
warfarin arm. Could you clarify that discrepancy?
DR. HORROW: If I may first address the
issue of the heterogeneity, then we can
go on to
88
the issue with EXULT.
If I'm not mistaken, you're
referring, in
terms of the heterogeneity in SPORTIF, to
what may
be called a study by treatment
interaction, the
difference in sampling and getting one
set versus
the other. And I think it's important to
understand that in each case,
noninferiority was
satisfied; that is, looking at the data
just in
those terms and how those numbers are
sorted does
not take into account the noninferiority
design of
the trials and that the success is
determined by
whether or not it meets the
noninferiority
criterion.
The heterogeneity result which
we've
looked at is not robust to sensitivity
analyses
like the primary results are robust. So, for
example, if one looks at primary events
plus
all-cause mortality, which was an
endpoint
suggested by the agency, the
heterogeneity
disappears and the p value is 0.23. And if you
look at other prespecified outcomes, such
as major
bleeding, there's no suggestion of
disparity there.
89
The heterogeneity p value is 0.81. For total
bleeding it's 0.275.
And so we view the idea of
disparate
results in the two trials with some
suspicion and
think that we need to be very careful how
we
interpret those primary results in terms
of being
disparate or the same. We view them as sampling
from the same pool and getting two
separate results
and that the best estimate of the data
comes from
pooling.
I'd like now to--
DR. FLEMING: Given that you didn't answer
my question and you provided a different
answer,
let me respond to the answer you just
gave. The
question that Steve asked is why was
there such
heterogeneity in relative risk
estimates. The
answer that you gave was there's a lot of
heterogeneity in the control arm, in the
warfarin
rates across trials. Logically, I would assume
that if you're saying when the warfarin
rate in
truth is different across trials, we
should expect
a
different treatment effect, it really makes me
90
worry about doing a noninferiority trial
where you
have to rely on historical evidence.
Could you answer, though, the
question
that I'd asked here about the discrepancy
between
your data here and the FDA briefing
document?
DR. HORROW: I'd like to ask Dr. Scott
Berkowitz, who was the medical person for
this
particular trial, to address this issue.
DR. BERKOWITZ: Yes, Scott Berkowitz,
AstraZeneca. I just wanted to say in terms of the
venography rate--I have the data to show
you, but
in terms of venograph, these two trials
had the
highest adequacy of evaluability ever
done in
clinical trials for pivotal purposes.
DR. FLEMING: That may be, and yet the
reality is we're still lacking 15 to 20
percent of
our randomization cohort, and we no
longer are
assured of integrity of
randomization. So could I
get the answer to my question?
DR. BERKOWITZ: So for what you saw, those
data that you saw in the briefing packet
were for
the overall study, so you can see it's
ten and
91
four, but I'm going to--could I have the
next
slide?--show you the breakout for
treatment, which
is the primary endpoint--
DR. FLEMING: So, in fact, what I do want
is the entire study, ten and four. So is the
clarification CE-19, then--
DR. BERKOWITZ: Could we go back?
DR. FLEMING: Then the reason CE-19 is
leaving out the five deaths and one death
is that
those occurred in the non-80, 85 percent?
DR. BERKOWITZ: The deaths--I'm sorry.
Say that again? I'm sorry.
DR. FLEMING: What is the reason that your
slide here leaves out five deaths and one
death?
DR. BERKOWITZ: That slide showed the
primary endpoint which included the
treatment
period of day 7 to 12 days as opposed to
the
overall, which showed only this study and
the next
one, if you want to see the breakout.
DR. FLEMING: Good.
And so that is--could
you show it again?
DR. BERKOWITZ: Oh, yes.
Can I see the
92
next one?
Thank you. We want to see now the
breakout between the treatment--
DR. FLEMING: So that the total deaths are
as here, they are as there in the FDA
briefing
document, ten against four in the wrong direction.
And pulmonary embolism is, according to
the FDA
briefing document, four against five as
reported by
the FDA.
DR. BERKOWITZ: Yes.
Well, you can see
down--for the treatment period, as you
can see,
there was one in the ximelagatran 36 group
and none
in warfarin. During the follow-up period, there
were four in the ximelagatran group and
zero in
warfarin.
DR. FLEMING: And so in an ITT analysis
that does include all patients and
focuses on,
among the most clinically relevant
endpoints, death
and pulmonary embolism, it appears that
there are
actually numerically an excess of events
in the
Exanta group. By my count there are 15 events
against 10 events, and that's your
numbers as well.
Is that correct?
93
DR. BERKOWITZ: Well, except that the
numbers that you're seeing in follow-up
are after
patients are off treatment but they get
seen in 4
to 6 weeks.
DR. FLEMING: I want ITT, and that's what
it looks like. Is that correct? It's 15 against
10 in the wrong direction? Just is the FDA summary
correct on page 26?
DR. BERKOWITZ: Yes.
DR. FLEMING: And one other quick
question, if I could. Again, wanting to try to
focus on an ITT of a critical endpoint,
all-cause
mortality, in THRIVE III could you show
us the ITT
summary?
This is the placebo-controlled trial
where we see a substantial efficacy
result on the
symptomatic endpoint. Could you show us the ITT of
the survival curves for that trial?
DR. BERKOWITZ: I'm not
certain--did you
want to see the slide that we showed for
the
original presentation?
DR. FLEMING: I believe it's corresponding
to the page 7, Figure 1 in your briefing
document.
94
DR. BERKOWITZ: Let me bring that up. I
just want to be sure it's the same one
that we saw.
DR. FLEMING: The one that I am in
particular looking for here, because that
figure
includes all the data from all the
trials, is in
particular THRIVE III with ITT analysis
of
mortality over the time frame that you
followed
these patients.
DR. BERKOWITZ: Yes, okay, and that's what
we were--yes, I'm sorry. So here you go. This is
the slide.
DR. FLEMING: Mortality.
DR. BERKOWITZ: Yes.
DR. FLEMING: All-cause, ITT.
DR. BERKOWITZ: I'm sorry.
I still don't
understand what you--just the mortality
slide?
DR. FLEMING: Yes, as you have in Figure 1
of your briefing document.
DR. BORER: You wanted to see only for
THRIVE, or you wanted to for the--
DR. FLEMING: Either way, if you--okay.
DR. BERKOWITZ: This is the slide in the
95
briefing document that you're speaking of
with all
the mortality.
DR. FLEMING: Okay.
And could you--so the
THRIVE is, in fact, the--
DR. BERKOWITZ: I'm sorry, yes, the THRIVE
is the lowest curve there, the
ximelagatran versus
placebo in the lowest group.
DR. FLEMING: And so essentially, while
I'm focusing on THRIVE, the evidence here
would
suggest, even in placebo-controlled
comparisons,
there's strong suggestion of no
differences in
survival.
DR. BERKOWITZ: Well, I mean, they're
lower with the ximelagatran group, but
not a strong
difference.
DR. FLEMING: I'm sorry.
I don't--the
curves look overlapping in the THRIVE
III, and in
the
other studies they are very overlapping as
well.
DR. BORER: Steve?
DR. NISSEN: Yes, I just had one more
question, still trying to probe to
understand the
96
differences between SPORTIF III and
SPORTIF V.
Could you show us the INR values, that
is, the
degree of anticoagulation control in
SPORTIF III
and SPORTIF V for the warfarin arms.
DR. BERKOWITZ: I'll ask Dr. Jay Horrow to
present that.
DR. HORROW: I'm sorry.
I missed the last
two words in--
DR. NISSEN: Yes, I just want to see in
the warfarin arm of the trials, I want to
see what
the INRs looked like in SPORTIF III and
SPORTIF V.
DR. HORROW: Okay.
I believe these data
will address your question. There were almost
100,000 different INR values, and this
summary
perhaps helps. Here we have SPORTIF III and
SPORTIF V and the percentage of time in
specific
ranges.
DR. NISSEN: It does.
DR. HORROW: Okay.
Thank you.
DR. BORER: A final question of fact,
Jonathan?
DR. SACKNER-BERNSTEIN: I think the key
97
thing is that all of the slides that show
ITT are
not true ITT analyses. It's not just THRIVE. It's
THRIVE and EXULT, and they list that in
the
briefing document. There are a lot of numbers
where those are different, so we should
just
interpret it that way.
DR. FLEMING: It was part of the reason
for my asking the question. I wanted to get a
verification that we were being shown,
for
endpoints such as mortality, a true
ITT. And I
understand that they're telling us they
are showing
us a true ITT where you have uniform
follow-up
through a given calendar date at which
the study
data freeze would have occurred, and you
would have
complete follow-up on mortality for all
patients.
Is that what that Figure 1 showed?
DR. HORROW: Yes.
DR. BORER: Okay.
Thank you, Jay.
DR. HORROW: May I introduce Dr. Sunita
Sheth, who will discuss particular
aspects of
safety for ximelagatran.
DR. SHETH: Good morning.
I'm Sunita
98
Sheth, Senior Director of Clinical
Research at
AstraZeneca.
You've just seen the efficacy
data
supporting the benefit of ximelagatran as
an oral
anticoagulant. I'll now review the clinical safety
date.
The analysis comes from a large data set
with more than 30,000 subjects, many of
the
patients involved having serious
underlying disease
and receiving multiple drug therapy.
First, I'll discuss by
indication the
adverse events and bleeding
profiles. Efficacy for
any anticoagulant is balanced by risk of
bleeding.
Indeed, bleeding and the prevention of
thrombosis
derive from the same action of drug. That's why
bleeding was a prespecified endpoint in
the pivotal
trials.
And major bleeding was adjudicated in a
blinded fashion in all Phase II and Phase
III
trials.
Then I'll focus on two specific topics:
myocardial ischemic events and the
hepatic
findings.
Finally, I'll conclude with a review of
overall mortality and summarize the key
points for
each indication.
99
It may help if I display how
we've
organized the large data set. It divides logically
into three groups: Phase I, surgical, and
nonsurgical populations. The Phase I population,
composed primarily of healthy volunteers
dosed for
up to 8 days, didn't present any safety
signals.
Surgical patients, mostly from the
orthopedic
studies with dosing up to 12 days, have
different
safety issues, in particular,
perioperative
bleeding, and so they are reviewed as a
separate
group.
The nonsurgical population
primarily
received drug for more than 35 days and
provides
the core safety evaluation of long-term
dosing,
with exposure up to 4 years. Each population pool
is
large, allowing a detailed assessment of safety
in each case.
I will first review the safety
for the
surgical indication. The North American surgical
population has been termed "the
warfarin comparison
pool" and provides the safety data
for the
indication under consideration today,
with
100
post-operative dosing of either oral
ximelagatran
or warfarin after total knee replacement
surgery.
This pool includes data from three Phase
III
trials:
the two EXULT trials as well as an earlier
study evaluating 24 milligrams versus
warfarin.
Overall, it includes 5,236 patients.
In all graphs, ximelagatran
will be shown
in a shade of orange and the comparator
in gray.
Here's the summary of adverse
events for
the surgical pool. Both treatment groups showed a
similar frequency and type of adverse
events.
There didn't appear to be any dose
response
comparing the 24- and 36-milligram
doses. We can
look more closely at the EXULT trials
where both
major and minor bleeding events underwent
independent adjudication. Rates of major bleeding,
shown at the bottom of each bar, were 1
percent or
less in all treatment groups, with no
statistically
significant differences for major
bleeding alone or
for the combination of major and minor
bleeding,
for
which respective p values are shown.
When you look at the data for
the proposed
101
36-milligram dose, there wasn't a
difference in
surgical outcome parameters, such as
wound hematoma
or intra-articular bleeding. Additionally, the
proportion of patients receiving
transfusion and
the volume of transfusion were similar in
each
group.
Now, let me turn to the nonsurgical
patients who comprise the long-term
dosing group.
This group is called the long-term
exposure or LTE
pool, with patients from all the Phase II
and Phase
III studies conducted so far involving
dosing
beyond a month's duration. In addition to patients
from the atrial fibrillation and venous
thromboembolic secondary prevention
indications,
we've included data from two other
disease areas
where significant trials have been
conducted,
patients undergoing initial 6-month
treatment for a
venous thromboembolic event and patients
post-acute
coronary syndromes. The overall ximelagatran
exposure is substantial, a total of 6,768
patient
years, with a median exposure of 370
days.
Across this population, doses
between 20
102
and 60 milligrams have been used,
although the
majority of patients, 75 percent of them,
received
36 milligrams twice daily. The comparator group
includes both placebo as well as warfarin
and is
termed "the comparators'
group." In this group, 20
percent of patients received placebo.
I'll now comment on the different
indication pools.
In the VTE extended prophylaxis
pool, both
ximelagatran and placebo groups
demonstrate similar
frequency and types of adverse
events. The
incidence of serious adverse events and
discontinuations was actually lower in the
ximelagatran group compared to placebo.
In the same group, major
bleeding occurred
rarely, affecting six patients in the
ximelagatran
group and five patients in the placebo
group.
Ximelagatran and placebo groups also did
not differ
with respect to major or minor bleeding
events.
In the atrial fibrillation
pool, the same
frequency and types of adverse events
were recorded
in both the ximelagatran and warfarin
groups.
103
Discontinuations were higher in the
ximelagatran
group, not because of symptoms but mainly
due to a
protocol-mandated discontinuation for ALT
elevation. I'll discuss this in detail shortly.
In the atrial fib population,
the rates of
major bleeding with ximelagatran did not
differ
from those with warfarin. Minor bleeding events
occurred quite often in these trials and
for that
reason did not undergo adjudication. Here we see
the event rates for patients with one or
more major
or minor bleeding events. Total bleeding occurred
significantly less often with ximelagatran
than
with warfarin, with a p value of less
than 0.001.
Overall, with regard to adverse
events and
bleeding, ximelagatran compared to
well-controlled
warfarin following total knee replacement
surgery,
compared to placebo and extended
secondary
prophylaxis of VTE, and compared to
warfarin in
atrial fibrillation patients demonstrated
no
important differences in adverse events,
bleeding
profile, or the safety profile of the 24-
and
36-milligram doses. In addition, a detailed
104
subgroup analysis for bleeding supports
the
proposed fixed-dose approach for all
types of
patients studied.
I'll now review two special
safety topics,
coronary artery disease and the hepatic
findings.
First let's address the coronary artery
disease
findings.
The agency has noted a possible
imbalance
in the frequency of myocardial
infarctions. Shown
here is Table 12 from the FDA briefing
document.
The events shown here are
investigator-reported
events.
Note that the absolute number of
myocardial infarctions observed in the EXULT
trials
was small, and there appears in a
post-hoc analysis
to be a significant difference with a p
value of
0.049.
However, this difference is driven by a
single trial, EXULT A. Furthermore, an analysis of
other coronary artery disease events
failed to
reveal any significant difference.
FDA Table 40 shows
investigator-reported
coronary adverse events from selected
trials from
the long-term pool. This analysis suggested an
105
increased frequency of total coronary
adverse
events in the VTE treatment
population. When VTE
treatment and extended prophylaxis are
evaluated I
a post-hoc pooling and analysis, the p
value is
significant for both myocardial
infarctions and
other coronary artery disease
events. However,
this finding was not observed in the much
larger
atrial fibrillation pool. In addition, the trial
in acute post-coronary syndromes where
benefit was
demonstrated is not included in this
analysis. In
fact, when all three groups are pooled,
no
significant difference is observed for
either
myocardial infarctions or other coronary
events.
In addition to the
investigator-reported
events, the SPORTIF trials in atrial
fibrillation
with an active comparator, warfarin, and
the ESTEEM
trial in the post-ACS setting versus
placebo
provided an independent and objective
assessment of
myocardial infarctions. In fact, adjudicated
events in these trials represent over 90
percent of
all MIs across the program. Here, evaluation of
the SPORTIF trials demonstrated an
identical
106
incidence while the ESTEEM trial
demonstrated an
actual reduction in myocardial
infarctions.
It is also relevant in this
context that
across the whole program we have no
evidence of any
rebound effects producing MIs after
ximelagatran
treatment was stopped.
So with regard to coronary
artery disease
adverse events, while a concern was
raised
regarding a potential imbalance in
events, a more
comprehensive analysis focusing on both
investigator-reported and objectively
assessed
events fails to identify an increased
risk.
I now want to turn to the
unexpected
results, the hepatic findings, and present a
detailed review.
We've taken the findings very
seriously,
and from the large database individual
case
analysis and consultation with hepatic
experts,
we've produced a thorough
assessment. I'll first
review the laboratory findings followed
by the
adverse event data.
Preclinical toxicology and the
Phase I
107
studies did not demonstrate any hepatic
safety
issue.
The surgical studies with up to 12 days of
dosing didn't show any hepatic changes
with
ximelagatran, just the well-recognized
enzyme
elevation seen with heparin. In the first Phase II
long-term dosing study with ximelagatran
in the
atrial fibrillation patients, a signal of
an
asymptomatic increase in ALT greater than
3 times
the upper limit of normal was noted. Therefore,
the standard laboratory testing that was
being
performed early in the development
program was
increased in the Phase III studies.
The liver function testing
panel consisted
of alanine amino transferase, or ALT;
aspartate
aminotransferase, or AST; alkaline
phosphatase, and
total bilirubin. These tests were performed
monthly for the first 6 months of
exposure, then
every 2 months up to one year, and then
quarterly.
In addition, weekly testing and
discontinuation
criteria were defined. These criteria were
strengthened after one case of
biopsy-documented
hepatic necrosis.
108
As mentioned, there was no
increase in ALT
greater than 3 times the upper limit of
normal in
ximelagatran patients undergoing total
knee
replacement compared to warfarin during
treatment.
At the 4- to 6-week follow-up, there were
eight
patients in the ximelagatran group and
three in the
warfarin group that developed an increase
in ALT.
In general, these increases occurred 3
weeks after
discontinuation of drug. It's important to note
that two patients with the transaminase
elevation
in follow-up in the ximelagatran group
had received
low-molecular-weight heparin. The ALT elevation in
all patients but one in each group is
documented as
resolved.
We believe that patients undergoing
orthopedic surgery with short-term dosing
of
ximelagatran are not at an increased risk
of ALT
elevations or liver injury.
Now, let me summarize the
incidence of
enzyme elevations of the long-term
exposure pool.
The incident of ALT greater than 3 times
the upper
limit of normal was 7.9 percent for
ximelagatran
compared with 1.2 percent for
comparators. It's of
109
interest to note that there was no
difference
between groups for isolated elevations of
bilirubin. The vast majority of these enzyme
elevations were asymptomatic.
Our experience shows that the
time
signature for ALT elevation follows a
consistent
pattern.
This graph depicts the number of patients
with first ALT greater than 3 times the
upper limit
of normal over time. The y axis represents the
cumulative risk of an ALT greater than 3
times the
upper limit of normal and the x axis time
in
months.
As can be seen, the occurrence increases
above background rates after 1 month and
approaches
background rates after 6 months. Ninety-three
percent were detected during the first 6
months,
and 98 percent within the first 12
months.
I now want to turn to the
disposition of
patients with an ALT increase. Of the 546 patients
in the ximelagatran group that had an
increase to
greater than 3 times the upper limit
normal, 46
percent of patients continued to
treatment and
completed the study. The other 54 percent
110
discontinued study drug. Overall, 96 percent of
ximelagatran-treated patients returned to
less than
or equal to 2 times the upper limit of
normal ALT,
regardless of continuation or
discontinuation of
drug.
Of the 74 patients in the comparator group,
31 percent continued treatment, and the
other 69
percent discontinued treatment. Overall, 93
percent of comparator-treated patients
recovered.
The algorithm allows
continuation of
treatment for mild and transient
increases on drug.
These data demonstrate the reversibility
of the ALT
increases.
Patients who continued drug
recovered by a
median of 28 days, and those who
discontinued drug
by a median of 40 days. Eighteen patients were
rechallenged early in the program. Only two
patients had a subsequent ALT rise. One pt with a
peak ALT of 10 times the upper limit of
normal was
rechallenged after 65 days and did not
have a
repeat elevation until 2 months
later. The second
peak was at 3 times the upper limit of
normal, and
the drug was discontinued.
111
The second patient did not have
a true
rechallenge, but had multiple episodes
above 3
times the upper limit of normal, but
overall
recovered with continuation of the
drug. There was
no evidence in these or any other
patients for an
immunoallergic response.
Hepatic experts that we
consulted
suggested that the elevation of ALT
greater than 3
times the upper limit of normal and
clinical
jaundice, in the absence of an
alternative
diagnosis, can be considered a signal of
severe
hepatic injury. We selected a more conservative
definition to standardize the levels and
timing and
included cases with ALT greater than 3
times the
upper limit of normal and bilirubin
greater than 2
times the upper limit of normal, the
latter
occurring within one month of the ALT
rise.
A total of 37 patients, or 0.53
percent,
in the ximelagatran group had this
concurrent
elevation of ALT and bilirubin, compared
with five
patients in the comparators' group, with
an
incidence of 0.08 percent.
112
Please note that one additional
case has
been included in this analysis at the
request of
the FDA.
We had fully documented this case
involving a fatal GI bleed in the
submission and
had also highlighted it as a case of
interest in
the safety review.
I'll now review the outcome in
patients
with a concurrent increase in both ALT
and
bilirubin. Confounding diagnoses were noted in 25
of the 37 patients on ximelagatran. Seven patients
in the subset died of unrelated
causes. Twelve
patients did not have an alternative
diagnosis for
the enzyme elevation. Of these 12, two died with a
GI bleeding event and will be discussed
shortly.
The ALT and bilirubin in all other
patients
recovered. Of the five cases in the comparator
group, four had an alternative diagnosis,
and only
one had an unexplained increase. Two patients died
from pancreatic cancer. The other patients
recovered.
We have been investigating a
possible
mechanism for the hepatic changes, but so
far this
113
has not been elucidated. Preclinical studies
evaluating reactive metabolites,
mitochondrial
dysfunction, and protein binding have not
been
revealing. There is no evidence for involvement of
the P450 system. The asymptomatic and
nonprogressive pattern of ALT increase
has been
noted with other drugs, including
tacrine, INH,
amiodarone, among others.
We wanted to understand if
there's a
subgroup that's at increased risk. Because the
number of patients with concomitant ALT
and
bilirubin is so low, this analysis was
performed on
the occurrence of ALT greater than 3
times the
upper limit of normal. Therefore, these results
should be interpreted with caution. A step-wise
logistic regression was performed looking
at
demographic factors, statin use, and
baseline
disease.
As expected, the most significant factor
in this analysis was ximelagatran
treatment with an
odds ration of 6.82.
Other factors that demonstrated
statistical significance all had an odds
ratio of
114
less than 2. These includes patients post-ACS,
patients being treated for an acute
venous
thromboembolic event, body mass index
less than 25
kilograms per meter squared, and female
gender.
Statins and creatinine clearance were not
identified as significant factors.
The variable of ALT greater
than 3 times
the upper limit of normal is generally
asymptomatic
and reversible. Therefore, this analysis does not
allow a prediction for those at risk for
severe
liver injury. We are, therefore, recommending ALT
testing for everyone who starts long-term
treatment
with ximelagatran.
Now let's look at the adverse
event data
from these patients. No difference is noted
between groups for clinical hepatobiliary
adverse
events.
T2B I will now briefly review
three selected cases in the group of
patients with
concomitant increase in ALT and bilirubin
associated with ximelagatran. These cases were
selected by the FDA as three deaths with
associated
115
severe liver injury. The first two cases occurred
on the first algorithm, and the third
case on the
second more conservative algorithm. The second and
third case did not demonstrate compliance
with the
algorithm in effect at the time. The deaths in all
three cases are also confounded by other
factors.
In the first two cases, the ALT
and
bilirubin increase was unexplained, and
the
terminal event in both cases was a GI
bleeding
event.
The first patient, an
80-year-old male,
had a hepatic biopsy with documented
hepatic
necrosis about 1 month before death. This patient
had evidence of decreased hepatic
function.
However, the ALT was recovering when he
died from a
perforated duodenal ulcer. This patient had been
on prednisone.
The second case presented
hypertensive to
the hospital with an elevated ALT of 11
times the
upper limit of normal and a bilirubin of
1.4 times
the upper limit of normal after missing
two weekly
tests for an elevated ALT. The INR was 3.4 and the
116
APTT was 69 seconds. His last dose of ximelagatran
had been earlier that evening. The patient had a
prior history of duodenal ulcer and
Bilroth II
anastomosis with bleeding at the site
detected on
this admission. During the 24 hours from the
admission to death, the patient received
massive
transfusions. During this time his bilirubin
increased from 1.4 times the upper limit
of normal
to 9.4 times the upper limit of normal,
with 50
percent noted as indirect bilirubin. At the time
of death, the bilirubin was 7.3 times the
upper
limit of normal and the ALT less than 2
times the
upper limit of normal.
The third case was a death due
to
fulminant reactivation hepatitis B with
an elevated
ALT upon study initiation. This patient was on two
immunosuppressive drugs: prednisone and
azathioprine. Ximelagatran was not discontinued
when the ALT reached greater than 5 times
the upper
limit of normal as recommended. The patient had a
rapid and fulminant course attributed to
the
hepatitis B. However, the investigator could not
117
rule out that the drug did not contribute
to the
fulminant course.
To summarize the hepatic findings, ALT
elevations greater than 3 times the upper
limit of
normal occurred in 7.9 percent of
ximelagatran-treated patients, occurring
primarily
within the first 6 months. The elevations were
typically asymptomatic and reversible,
without any
evidence of an immunoallergic
reaction. An
incidence of 0.5 percent of concurrent
ALT greater
than 3 times the upper limit of normal
and
bilirubin greater than 2 times the upper
limit of
normal was observed. Exposure response suggests
that exposure is not predictive of
individual risk
of transaminase elevation, and no patient
subset
was identified to be at higher risk of
developing
severe hepatic injury.
Based on the data, we are
proposing ALT
testing in the label reflecting the more
conservative testing schedule used in
clinical
trials.
To make sure that ALT testing becomes the
standard of care with ximelagatran, we
also
118
submitted a risk minimization plan which
set out
our initial proposals to support ALT
testing in
practice.
This proposal was developed after
extensive external consultation and field
testing,
but we recognize that it may need to be
developed
further in the best interests of ensuring
patient
safety.
We have a meeting arranged with FDA on
this topic in the near future.
A few comments on the
principles of our
Risk Minimization Action Plan. The ultimate goal
of the plan is to prevent any hepatic
failure
caused by treatment with
ximelagatran. To do this,
the Risk MAP will help to ensure
compliance with
labeled ALT testing recommendations. This proposal
was developed to provide access to
ximelagatran by
those patients who will benefit while
minimizing
risk.
It targets patients, physicians, and
pharmacists. It has a strong educational focus and
is enhanced with practice management
tools and
special packaging. In addition, following
discussions with FDA, AstraZeneca will be
proposing
additional enhancements to ensure our ALT
testing
119
recommendations are followed. Finally, we have
proposed continuous evaluation of program
effectiveness.
AstraZeneca understands that
the full
benefit of ximelagatran can only be
realized if it
is used in accordance with the labeled
recommendations, and
to that end we are committed to
developing the specifics of the program
in
consultation with the agency.
To complete the assessment of
safety, we
will finish with the overall mortality in
the
long-term exposure pool to get an
overview of risk.
The patient population was primarily an
elderly
population with multiple comorbidities
and
concurrent medications. Despite an increase in ALT
in the ximelagatran-treated patients, no
difference
in all-cause mortality was noted. Mortality was
similar in the ximelagatran group compared
to
patients on placebo, patients on placebo
plus
aspirin, and patients on warfarin.
Let me finish by summarizing
the
benefit/risk comments for each
indication.
120
Ximelagatran prevented venous
thromboembolism
and/or all-cause mortality compared with
warfarin
in total knee replacement surgery with a
number
needed to treat of 12. No difference was seen in
bleeding, transfusions, or surgical
outcome.
Ximelagatran demonstrated clear
benefit
over placebo with a number needed to
treat of 10 in
the long-term prevention of recurrent VTE
events.
This included a clinically important reduction
in
pulmonary embolus, a condition that can
result in
serious morbidity and mortality. The incidence of
bleeding was comparable to placebo.
Ximelagatran was as effective
as warfarin
in reducing the risk of stroke and other
thromboembolic events in patient with
atrial
fibrillation. Bleeding was lower on ximelagatran.
With regards to the hepatic findings,
while the
risk per year for stroke or venous
thromboembolism
is continuous, the risk for an ALT rise
and
subsequent severe liver injury is limited
primarily
to the first 6 months of ximelagatran
therapy. But
the protection from a thrombotic event by
121
ximelagatran is continuous and consistent
over
time.
To aid effective management of
the hepatic
risk, ALT testing will be recommended in
our
proposed labeling, and in addition, we
have
submitted a Risk Minimization Action Plan
which we
will discuss further with the FDA.
We conclude that ximelagatran,
the first
new oral anticoagulant in over 50 years,
does have
a positive benefit/risk in each proposed
indication
provided that the drug is used
properly. We look
forward to your comments and further
dialogue with
the agency.
Thank you. I'll take questions.
DR. BORER: Dr. Sheth, I think we need to
take a break. I've been chastised when we haven't
done that. So we'll take a 10-minute break, and
then we'll go on to the questions of fact
about the
safety data, and I think we can then go
on to
Jonathan Halperin's presentation, and
we'll just
make up the remaining FDA time after the
public
comments later so that you can get your
whole
122
presentation in.
So we'll take a 10-minute break
right now.
Look at your watch because 10 minutes
from now
we're going to start again.
[Recess.]
DR. BORER: While everybody is getting
back in here and sitting down--or not
sitting
down--let me raise an issue for you to
begin to
think about as people are coming back in.
Steve Nissen asked earlier
about
pharmacological evidence of rebound, and
there
didn't appear to be significant rebound,
although I
don't know what that means in the context
of
studies with limited power. But there didn't seem
to be significant rebound of
pharmacological
effects, although the follow-up, as I
recall, was
relatively short. So we don't know about late
pharmacological changes. But as I look at these
data from each of the trials, I'm struck
with a
difference between the on-treatment and
post-treatment frequency of major adverse
cardiovascular events that I'd like to
hear some
123
discussion about from you. Is this real or is it
not?
That is that if you look at the number of
myocardial infarctions or other cardiac
events that
occurred on ximelagatran versus the
comparator, the
numbers were different but not all that
different.
It depended on the trial. It varied from trial to
trial, and we can talk about that
potential adverse
event disparity later. But I'm concerned or I want
to ask about something else.
If you look at the number of
events that
occurred on-treatment, the numbers were
relatively
close one way or the other from trial to
trial to
trial.
If you look at the numbers that occurred
post-treatment, the proportion of
patients who had
events on ximelagatran in the
post-treatment period
was greater as a percentage of the whole
than was
the case for any of the comparators. The
post-treatment events on warfarin or on
placebo
were fewer as a proportion of the whole
of the
total number of events in those
comparator groups
than was the case with ximelagatran, and
in some
cases the post-treatment events were more
frequent
124
than the on-treatment events with
ximelagatran.
That's an observation.
Have you noted that? And is that true?
And do you have anything to say about it?
DR. SHETH: The numbers differ a little
bit between the different patient
groups. So let
me start first with the long-term
exposure pool and
some of the specific populations within
that pool.
If we can take a look again at
the--and
we're talking coronary events, Dr. Borer?
DR. BORER: Yes, we can limit it to
coronary events, however they're defined.
DR. SHETH: What you see is that, you're
right, there is a difference--I'm
sorry. Let's put
that up.
You do see an increase--and these are
both myocardial infarctions and total
other
coronary artery disease events other than
MI
compared in the VTE treatment and the VTE
extended
prophylaxis compared to warfarin. But these
numbers are actually quite small. We're talking
about a total of 16 patients here, 3, 16,
10, et
cetera, versus 1, 0, 12, 3.
125
If we take a look at two
populations where
you might say that the risk is actually
increased,
the atrial fib group had higher incidence
of both
diabetes, hypertension, for example. You don't see
that--those events, again, plus that in
the
post-acute coronary syndrome population,
which is
certainly a high-risk group for
events. Can we
take a look at the next slide? I'll come back to
the after-treatment in a second.
Ninety percent of the MIs--and
this was
during the trials--occurred in these two
settings,
and you don't see a difference there, and
you see a
benefit on treatment with ximelagatran.
But if we take a look, let's
say, at the
post-acute coronary syndrome population,
again, a
higher-risk group, after treatment
stopped, the
incidence between those two groups was
about 1.5
percent--I think it's about 1.5 percent in
both
groups.
DR. BORER: Okay.
I'm sure you're right,
and the data you just showed I think are
very
reassuring, and I think we all saw them
in the book
126
here.
But, again, I'm making a slightly different
point, and maybe the data aren't
available or
aren't sufficient to draw a firm
conclusion about
them.
What I am talking about is the
proportion
of coronary events that occurred after
stopping
treatment on ximelagatran as a percentage
of the
total number of events compared with the
portion
that occurred after stopping treatment
with
warfarin or placebo as a percentage of the total
number of events in those groups. I believe that
the proportion of events that occur
post-treatment
is higher in the ximelagatran groups
across all the
trials, if you look at trial after trial,
than is
the case for the comparators, which
raises some
question about the possibility of a
rebound
phenomenon or something else, some other
pathophysiological process that's being
allowed to
happen or occurring because of the use of
the drug
once it's stopped.
DR. SHETH: I understand what you're
asking.
We don't have that specific analysis, so I
127
won't be able to address it at this
moment. You're
asking for those proportions of patients
after they
stop treatment over the total number of
events, and
right now I don't have that analysis.
DR. BORER: Okay.
You can pull it
together later, but it's in the
books. If you look
at the data that are presented, if you
look at the
numbers, that sort of jumps out at
you. So you may
want to look at that, and you can talk
about it
after lunch or something.
DR. SHETH: Okay.
DR. BORER: Okay.
Well, why don't we go
on and see--Alan?
DR. HIRSCH: Well, just one comment to
follow up Jeff, and if you're able to
provide that
after lunch, I specifically would ask you provide
that not in the ACS population, because
the
population that will be exposed to this
if this
drug comes to market that really is
vulnerable that
I'm concerned about is that non-ACS
population.
DR. SHETH: Okay.
DR. HIRSCH: I don't want that to be a
128
Band-aid for a potential adverse effect.
DR. BORER: Steve and then Bill.
DR. NISSEN: Just so you understand what
we're concerned about--and several of us
have made
this observation--it is that because
ximelagatran
is a short-acting agent compared to
Coumadin, our
worry is that when you stop the drug,
there's some
phenomenon that goes on for a few days or
a few
weeks in which a patient has increased
vulnerability and
that that is the explanation for the
excess cardiovascular events. And we want to
understand whether you have some response
to that
that we can factor into our thinking.
DR. SHETH: Can I ask, would it help the
committee to take a look at other
thrombotic events
in terms of incident or rebound
phenomena? Because
certainly patients who are usually at
risk for
venous events might typically get those
kind of
events.
Would that help--
DR. NISSEN: It only helps a little bit.
The problem is that the pathophysiology
of arterial
and venous events are different.
129
DR. SHETH: Right.
DR. NISSEN: And so, you know, it appears
that there is this excess of arterial
thrombotic
events post-treatment, and we're trying
to
understand that in order to factor that
into the
thinking here of the committee.
DR. SHETH: Right, although in maybe the
treatment and prevention groups--
DR. NISSEN: Yes, yes.
I have another
question, and forgive me for this, but I
have to
probe on something that I think is
important. If
you could put up Slide No. CE-19,
please? I see
these patients that are going to have
knee
replacement all the time in
consultation. They
almost all get sent for cardiac clearance
because
they're older and they have a lot of
cardiovascular
risk factors, and I'll bet the other
cardiologists
at this table, like Jeff probably sees
plenty of
these as well. And so when I see them, there are
three things that I worry about. I worry about, of
course, them dying. I worry about them having a
pulmonary embolus. And I worry about them having a
130
myocardial infarction.
And so, you know, to do the
simple math
here, which is what all of us are kind of
looking
at, if you look at the serious endpoints,
the
feared complications, what you see is--in
EXULT A
and B, you see three plus six is nine
events with
ximelagatran, and you see eight events
here, PE or
death, with warfarin.
If you now put up Slide No.--
DR. FLEMING: Steve, just before you go,
those nine and eight are 15 and 10 in the
FDA
briefing document. It's worse than this. It's 15
and 10.
DR. NISSEN:
Okay. I'm trying to be--you
know, not make this any more painful than
it has to
be.
Now let's look at Slide CS-14,
so we'll
take nine and eight, so CS-14, and now I
look at
myocardial infarction, and it's 16 to
4. And so
when you put it together, you know, you
see that
the really serious events, the bad things
that can
happen to that patient I'm seeing in
consultation
131
look a lot worse on ximelagatran than
warfarin.
And so one has to ask the question: Does it really
look as good as it looks?
And so what are your thoughts
about this?
I mean, MI is as bad an outcome as PE,
isn't it?
DR. SHETH: Yes, it is.
In considering
those numbers, I won't dispute how--the
numbers
that we just looked at, they are higher
in the
ximelagatran group compared to the
warfarin group
in the orthopedic surgery
population. The only
comment I'd make is that,
unfortunately--those are
really small numbers, and the question
is: Is this
a really--a true difference? And I would
anticipate that if it was a true effect that
we
would really see a significant effect in
the
long-term group just because it's so much
larger.
We also have another study that
we started
to do in extended prophylaxis in
orthopedic
surgery, so we'll be able to collect more
data in
that study as well. But, again, the numbers are
small so it's hard to know if this is a
true
difference or not.
132
DR. NISSEN: But, of course, the
difference in the long-term studies is
that this is
one where you get the short-term
administration,
then you withdraw the drug, and so it
speaks more
to this question of an acute rebound sort
of
phenomenon.
I mean, I hope you can appreciate why
it's something that really struck many of
us on the
committee as being a problem.
DR. BORER: It's also a potentially
remediable problem, so it's important
that you
should know about it.
Bill, and then Beverly.
DR. HIATT: Yes, just to follow up on
that, it does seem like the surgical
population may
not be the same as the long-term
treatment
population, and the concept of risk
occurring--excess risk occurring in that
population
is very real.
Then the other question I have
is, turning
to the SPORTIF IV data, you didn't
present that in
any of your safety data. Is that correct?
DR. SHETH: The SPORTIF II and IV data are
133
actually pooled in the atrial
fibrillation pool
that we performed. So it included that Phase II
trial, yes.
DR. HIATT: If you look at page 97 of the
briefing document, there are several
phases to
SPORTIF IV, and I count a total of 17
deaths on
treatment versus warfarin is four. So you're
saying those deaths are included in the
overall
safety data you presented?
DR. SHETH: They are included, but I'll
just point out that there are about 2 to
3 times
more patients on--3 times more patients
on
ximelagatran than on warfarin in SPORTIF
IV. So
they're not balanced groups. The denominators are
not balanced.
DR. HIATT: Correct.
DR. SHETH: But those deaths are included
in the atrial fib pool and consequently in
the
long-term exposure pool.
DR. HIATT: Okay.
DR. BORER: Beverly, and then Dr. Sjogren.
DR. LORELL: To follow up on this concept
134
of potential rebound--
DR. SHETH: Can you speak louder?
DR. LORELL: Yes, I can.
To follow up on
the issues that were raised about
potential rebound
in the post-surgical population, can you
enlighten
us as to how investigators were
instructed to use
or no instructions on aspirin? Was aspirin
deliberately not used in that surgical
population?
And then were there any instructions at
the
termination of treatment?
DR. SHETH: Let me ask Dr. Berkowitz, who
was the physician for those studies, to
describe
the use of aspirin instructions for the
surgical
population.
DR. BERKOWITZ: Scott Berkowitz,
AstraZeneca. I didn't get the second part. The
first part was that aspirin was
precluded, kept to
a minimum, and patients weren't to be on
it
routinely.
DR. LORELL: So I think the second part,
was there a strategy in that trial when
the study
drug was stopped about reinstatement of
aspirin in
135
patients who had risk factors? You know, the point
that Dr. Borer made, this is a group with
rich risk
factors.
DR. BERKOWITZ: I'm sorry.
I think I got
all your question. The studies were designed to
leave to the discretion of the
investigators to put
the patients back on the medicine, so we did
not
prespecify how to do that.
DR. LORELL: Okay.
And related to that,
have you done any studies after
withdrawal of the
drug to look at what happens to platelet
function?
DR. BERKOWITZ: In our clinical trials for
VTE and orthopedic surgery and I believe
in the
atrial fibrillation trials, we did not do
any
platelet studies.
DR. SHETH: I can mention we actually
looked and did an analysis of patients
both on
ximelagatran, on aspirin and off aspirin,
for
events in the atrial fibrillation
pool. If you're
interested, we can show that if that
would be
helpful.
And this is not exactly the same as the
patients who discontinued after
orthopedic surgery.
136
But if you're concerned about any
increased
beneficial effect--let's see. Actually, what you
see is that there is an incremental
benefit in
patients who are on aspirin, but you see
that same
benefit on warfarin, and you don't see a
difference
of the effect between the two
anticoagulants when
aspirin is added.
DR. BORER: The question that Beverly is
asking, though, is what about after
you've stopped
the ximelagatran and the warfarin. In that period,
were people still on aspirin or were they
not? And
did the fact that they were or weren't
have any
impact on the post-treatment events?
DR. SHETH: We didn't make specific
recommendations after the trial. They were to go
on their regular medications per their
physician.
DR. BORER: Okay.
Dr. Sjogren, then Alan,
then Ron.
DR. SJOGREN: My question pertains to the
potential hepatic toxicity, and I have a
couple of
questions. One is you are proposing to follow up
patients with ALTs, and then if they go
over 2
137
times the upper limit of normal, to
follow up a
little more closely and eventually
discontinue the
drug.
I'd like to know what kind of information do
you have in the patients that you
followed up that
developed the ALT abnormality to back up
that kind
of recommendation. That's one question.
The second question is: Do you have any
information on patients with chronic
liver disease
that are treated with this medication? What
happens to them?
And one request. Do you have slides of
the liver biopsy that was done that we
can look at?
DR. BORER: Before you begin to answer,
let me just state a rule here. We're not asking
you to tell us your algorithm for
following
patients.
Dr. Sjogren is just asking about the
data that might be used to inform the
development
of such an algorithm and then the issue
of the
chronic use and the slides.
DR. SHETH: Okay.
Let me answer the
latter two questions first, and I'm going
to have
to ask for a clarification on that first
one.
138
We do not have a slide of the
hepatic
biopsy right now. The chronic disease, because we
identified early in the Phase II trial,
SPORTIF II,
that there was this asymptomatic
transaminase
increase, we actually excluded patients
who had
known hepatic disease from the trials, as
well as
patients who had an ALT above 2 times the
upper
limit of normal. So that to the best of our
knowledge, patients who--with the
exception of the
reactivation hepatitis B, should not
have, in fact,
been enrolled in the trial, and we would,
in fact,
propose a contraindication for those
patients. So
we don't have data to understand the
safety in that
group.
In terms of follow-up, are you
asking
me--you want to know what did we do to
follow up
all patients who had an elevation or what
their
outcome was?